—is the continued strong performance of FILSPARI. We were able to reach nearly 2,000 new patients during the third quarter, and as we've seen in prior years, the summer months is often slower in nephrology, with fewer patients going to visit. That's exactly what we saw in the third quarter of last year, similar to the two prior years. But underlying that is a very strong continued demand for both IgA nephropathy, which is particularly important given the increased dynamism and the really exciting shift in the treatment algorithm for that condition, as well as now the continued strong uptake second quarter of our launch for FSGS. This is the only medicine approved for FSGS, and we're really just getting started with reaching many of those patients.
We reported $200 million in net revenue for FILSPARI in the third quarter, reflecting the very strong conversion of those patient start forms to paid prescriptions, again, reflecting the strong payer access that we have, not just in IgAN that we've been able to maintain, but also very quickly for FSGS. We also shared that our progress with pegtibatinase, our enzyme replacement therapy for classical HCU, is continuing to progress very well. Our HARMONY phase III study is continuing to enroll according to our timelines, and we're on track for data in the second half of next year. Our newest program, civorebrutinib, which is a BTK inhibitor that we in-licensed this year from Everest Medicines, we are on track to file IND and some of the enabling work for us to move quickly into later-stage development.
All in all, another very strong quarter of execution and puts us on track for where we hope to end the year in a very strong footing.
Okay, great. Thanks for that summary, and then let's dive a little deeper on the commercial side, then I'll turn to Arseniy to go a little deeper on the pipeline, which I think does seem like 2027 will be the year of pegtibatinase and the focus on the pipeline. On FSGS, you mentioned, you guys talked about on the call too, the start forms there continue to grow in this third quarter, the first full quarter for that indication. Can you just talk about what's driving the launch, where you're seeing the uptake, and then where do you see maybe more room for growth in these coming quarters?
Yeah, I think the key theme for the uptake that we've seen thus far in FSGS is the breadth of uptake, and that's both the breadth across the different types of FSGS. FSGS is quite different from IgA nephropathy, where there are different etiologies of FSGS, different types of patients across primary FSGS, genetic FSGS, and secondary. We are seeing broad use across those, and I think that's very encouraging because those patients all have very similar unmet need for better treatment. The other aspect of breadth is that we are seeing the broad use across nephrologists. I know that there were a lot of questions when we initially launched of whether this is going to be a bolus, whether it's going to be concentrated in certain physician practices, and that's just not the case.
We continue to see very broad prescriptions, which in a launch, you really want to be able to see, because once a nephrologist gets a good experience, they're more likely to extend the use into their practice and that depth of prescribing. So, what I'd say is that the uptake has been very encouraging for continued performance with FSGS, given those two factors of breadth.
Great. What do you think about the sort of competitive landscape here? Obviously, SGLT2s, there's other therapies these patients may be on, but specifically in FSGS, what are you seeing either in the near term or over the next few years as sort of the competitive landscape?
Yeah, there really isn't anything in the near future, unfortunately, for these patients. So, there will be a continued focus on us reaching these patients as urgently as we can. There are other therapies with different mechanisms, all complementary in the mechanism of FILSPARI, and so we actually do not see anything as a direct competitor. Many of the therapies that are in development may address certain segments of FSGS, whether it's a certain genetic subtype or immune-mediated, which is primary FSGS, but nothing really that we see yet evidence of breadth. There may be another therapy that could be broad, but again, very longer term in the future and also complementary to the role of FILSPARI. So from our perspective, that foundational positioning that we have in IgA nephropathy is what we expect well into the future for FSGS.
Okay. Great. Let's switch over to the IgAN side. How are you seeing the start forms trending so far? Maybe the fourth quarter will be a good start to build off of what you reported last week.
Mm-hmm.
Then, the summer seasonality that you talked about, and you talked about even ahead of the quarter, how did that sort of compare this year to maybe what you've seen in prior years in the IgAN space?
Well, we shared a little bit of commentary on our call last week. One, in terms of what we saw in Q3, was largely consistent with our experience in the summer months in terms of the magnitude of fewer patient visits, et cetera. But, I think certainly there is the perspective that the IgAN market is growing in dynamism. What I mean by dynamism is really physicians making an active choice to treat patients differently. Rather than continue them on ACE inhibitors, SGLT2s, or steroids, they're making an active choice to prescribe an approved therapy. We're seeing that really accelerate, and we're a very solid part of that new treatment algorithm.
Everything that we see is very much aligned with our expectations, and as I mentioned last week in terms of the start of Q4, we see continued strength in the prescribing, and everything that we see is very much aligned with our expectations.
Okay, great. You mentioned obviously a lot of new players coming into the space here. That was certainly a big theme of the ASN meeting last month. What are you seeing in terms of the unmet need now in IgAN, especially patients who may be either on FILSPARI and starting B-cell therapies or vice versa? How are you seeing this market sort of play out? Where's the need going forward?
Yeah, I think the need is very clearly laid out in the updated KDIGO guidelines, which anticipated this new set of treatment options, both in the kidney-targeted, like FILSPARI, as well as in the immune-targeted, like the B-cell therapies. The need is these patients need to have complete remission of their proteinuria, and the reason why that's important is any level of proteinuria is directly damaging to the kidney. Not only is it sort of the historical perspective of it's a marker of damage in the kidney, but any type of proteinuria above complete remission of 0.3 [g/day] actually continues to damage healthy nephrons and also can be cardiotoxic. So, it's really important that these patients have complete remission of their proteinuria, and that's now possible with these treatment options. For many patients, it's going to require combination.
The second aspect is stabilizing their eGFR, and that really has been a more challenging goal for the therapies that are available. That now seems to be possible, and we presented data at ASN that if you are able to get these patients earlier and in treatment-naive setting, they can actually achieve both of those with FILSPARI. So, as we look forward, the guidelines clearly lay out that patients should be on combination, and that's exactly what we expect. We're starting to see the early signs of that.
It's more likely going to be in the sicker patients that are going to be on combination first, but we do expect that as physicians become much more comfortable with all of these new therapies and understand how to sequence, many of the patients or most of the patients will be in combination of something like FILSPARI to target their kidney as well as an approved therapy to address their immune overactivation.
And maybe just building off that, this market and how it's emerging, maybe you can talk a little bit about that, like what you're seeing. There's certainly this move towards more combination use, but I think just more aggressive treatment of this condition overall.
That's right.
Are you seeing the market get much bigger now? I know you've thrown some numbers out in the past, but just given the entry of FILSPARI and now the new generation, is there more diagnosis, or is the overall addressable population maybe larger?
Yeah. What I would say is the furthest afield is going to be earlier diagnosis, which still requires a kidney biopsy. We are hearing anecdotally that nephrologists are more eager to biopsy patients that are fitting the profile of an IgAN patient, younger, generally healthier, but may have proteinuria, some hematuria, and so we expect that that's going to continue. The dynamics that we expected to see earlier, and that's exactly what we're seeing, is physicians that are much more aggressive in treating these patients.
They're no longer saying, I can accept a patient lingering at one or 2 g of protein for years and years. That, if you recall three years ago, four years ago, was really the biggest challenge that we at Travere wanted to overcome, is educate physicians and have evidence to say patients that may seem stable at one or 2 g of protein are at a very, very high risk of kidney failure within 10 years. That is now well accepted, and if you think about just in the last three years how that perception and that understanding has shifted, that's what's driving a lot of the uptake of the innovative therapies, including FILSPARI.
Okay.
Reaching these patients earlier, treating them, not lingering on ACE inhibitors, ARBs, and steroids for a long time. They are actively switching. When you look at just the overall PSFs that were reported across all of the approved therapies in the last quarter, it's clear signal that the dynamic market is growing, and it's in recognition that patients deserve better, and we now have better tools.
Okay. Then within your class, in terms of ERAs, Novartis also obviously a competitor there. Really was a couple options, I guess, ERA, because they also have the complement approach. But what are you seeing in terms of ERA specifically? How are physicians deciding between FILSPARI and VANRAFIA when they're thinking about an ERA for their patient with IgAN?
Yeah. I think for us, it's a very easy choice, and it's aligned to what we think patients want. Certainly, both of those therapies demonstrate the importance of addressing endothelin overactivation in the kidney and addressing the damage that's going on within the kidney itself. What we are seeing, however, is that when you have something like FILSPARI that replaces a medicine, the ACE or ARB that a patient is on, it actually signals the patient that they're winning because a patient is able to stop another therapy. We hear that often from patients saying, wow, I'm doing better on my proteinuria. Nearly every IgAN patient that I've spoken with, they know their proteinuria levels, and they know whether they're going in the right direction or wrong.
But they also say, I can stop a medicine. That really gives patients much more sense of control and optimism than adding and adding therapies. Pill burden is high. These patients are not just on therapies for their kidney, and often the average number of therapies an IgAN patient is on is five. So, pill burden really matters, and I think that's why we see very strong performance relative to the other therapy in this class.
Okay, great. Let me do one more, and then I'll turn it to Arseniy, actually.
Okay.
Because the question we get often is around the payer side. You mentioned more of this push towards combination use, which is in the guidelines. Are you seeing any sort of payer pushback at this point in terms of doctors needing to choose one branded therapy, whether it's from the same class or different classes?
At this point, no. We've been engaging with payers for a number of years. We've been talking about the evolution of this treatment paradigm for that long. We've also educated them on the data to show why complete remission is so important, and what the KDIGO guidelines recommend in terms of combination therapy. Essentially, every patient should be on combination. So, there's a recognition amongst payers. I think for us, we do not see pushback. We have very broad access. That has not changed over the years, including when the B-cell therapies have been introduced. In large part, we don't see pushback because, one, payers do have broad access for FILSPARI, but two, we're used much earlier. If we look at the prescriptions that we've received for FILSPARI just this year, FILSPARI is the first branded therapy that patient has ever received in 90% of those cases.
In other words, nine out of 10 patients have never seen a branded therapy. Their first introduction to an approved therapy is FILSPARI. We're being used early in that paradigm. We would not expect that pushback in terms of combination.
Interesting. Okay. All right, let me turn to Arseniy.
Hey, Eric. Could you talk about the unmet need in the classical HCU, and as you were thinking of making an impact outside of nephrology, why did you start with HCU?
Yeah. In classical HCU, these patients have an enzymatic defect of their CBS enzyme. Their CBS enzyme is responsible for metabolizing protein in our diet, and unfortunately, with that defect, which can be variable how much remnant enzyme the patient has, you start to see a toxic accumulation of homocysteine over a patient's life. For half of the patients, they're caught at newborn screening, and so their parents are able to manage their diet in a nearly protein-free diet, which prevents that accumulation of homocysteine over time. For patients that become adults and maybe are not as adherent to their diet, or for those patients that are missed at newborn screening, that homocysteine levels do increase pretty significantly in childhood, where around the age of eight, they start to get lens dislocation and eye problems, which may signal or prompt a diagnosis.
25% of them will have an ischemic event before they're a teenager, and half of them before they turn 30. It's a really devastating disease in terms of the outcomes if not managed effectively, and unfortunately, there's very little approved and available for these patients other than medical protein, high doses of vitamin B6, and betaine, which is effective for some patients, but certainly not the majority. That's a major challenge, is just the availability to control their homocysteine levels and prevent some of these clinical outcomes. But, one of the things that we hear so often from patients and their caregivers is just how much of a burden the diet itself is.
Imagine, as a kid, not being able to eat the same thing as your kids at school, at parties, at family gatherings. It's a real burden that can then cause a lot of the psychological challenges that these patients face of isolation, depression, anxiety, all around something that we take advantage three times a day.
Mm-hmm. The standard of care you mentioned, it works poorly, or for some patients, it doesn't work at all, or?
That's right. Yeah, for some patients, it doesn't work at all, and less than maybe about 40% of patients are considered vitamin B6 responders, and vitamin B6 is a cofactor for any residual CBS enzyme that you have in your body, so it'll help it be more effective. But even with that, patients oftentimes are not able to maintain control of their homocysteine. In the current guidelines, which is really based on limited clinical data, it's recommended that patients maintain their homocysteine levels to lower than 100 micromolar. But even with that, you still have a challenge because that assumes you have to maintain a very strict diet.
There is talk of trying to aim for lower, because it allows for the patients to be able to have some additional protein, whether it's a cheat day or whether they just are unknowingly consuming more protein. There's a bit of a buffer in wanting to do that. That hasn't been really achievable with what's available now. With pegtibatinase, based on what we've seen, it certainly is a strong potential.
Mm-hmm. Pegtibatinase is now in late clinical development. How are you thinking about the commercial opportunity and the number of patients?
That's right. We expect to have top-line data from our pivotal study in the second half of next year, designed very similarly to our phase I/II. As we look at the patient segment, the addressable number of patients within the U.S., and we define addressable by they need to have an actual diagnosis, they're under the continued care of physicians, which many patients are lost to follow-up because there really isn't much for them, and that's about 3,500 patients.
If we look to those patients that were missed at newborn screening and don't have a diagnosis, as well as those patients that have a diagnosis but just are no longer being seen by a physician. We can easily get to numbers of 10,000 to 12,000 patients, and we've been working for a number of years to be able to reach those patients through better newborn screening, earlier screening, as well as outreach for those patients that have a diagnosis, but felt like there was nothing left for them, other than being counseled on what they eat.
Mm-hmm. Great. Let's turn to civorebrutinib. You have an IND planned by year end, and what would the next steps after that be?
That's right. As we expect to file the IND this year, we also are expecting to do some additional bridging studies, so PK/PD, based in U.S. population, as well as some additional work on dosing to make sure that as we go into later stage development, we're really focused on the dosing that will work. There was some very solid work that was done by Everest that was in an East Asian population, so we want to make sure that we have data to be able to support all of the work that we'll be doing globally.
Mm-hmm. So this would be a phase II study, essentially?
We've not commented on that.
We're certainly —the other aspect, as you say, what are our next steps? It's continuing to look at what are the paths to be able to move quickly.
What are the endpoints, and continuing to engage with regulators to make sure that we are able to meet their needs, but also move very quickly.
Mm-hmm. I think you've shared that you would be focusing on primary membranous nephropathy as the first indication. Could you maybe just briefly talk about the unmet need in pMN, and what other options are available there, and what else is in development?
Yeah, absolutely. So you're right. Our first indication would be primary membranous nephropathy, we also have discussed our intent to go into immune-mediated FSGS as well as minimal change disease, which in many ways is similar to immune-mediated FSGS. When we look at primary membranous nephropathy, there are about 90,000 patients that we see broadly. We need to do the work to see what we see within that is addressable. But, a sizable rare kidney disease patient segment. When we look at this disease, these are patients that are quite symptomatic. These patients have issues with edema. 60%, 70% of them present with nephrotic syndrome, so very high proteinuria levels, as well as edema. So it is quite symptomatic. They will oftentimes describe brain fog because of their condition, as well as a whole constellation of other physical and psychological symptoms.
It is one where, when we think about the need, we think about how do we make sure that we can address the long-term challenges within the kidney. One of the things that was really interesting to us is the speed of onset. We want to be able to address the proteinuria as well as the symptoms quickly for these patients, just given how symptomatic they are. These patients oftentimes are on rituximab or other immune-targeted off-label therapies, that oftentimes are effective, but take a long time.
Those are some of the aspects as we thought about the ideal profile for a medicine for pMN.
Mm-hmm. Let me turn it back to Vamil.
Yeah, so we have a couple minutes left. Obviously one thing I did want to touch on is, you're personally leaving the company soon. First of all, congratulations on all the progress Travere has made over the last several years, especially the last few, with getting FILSPARI to the market for patients. Maybe you can just talk about Brad Campbell coming in as the new CEO on December 1st. Kind of what you can share in terms of the board and kind of how that decision was made to have Brad take over, and what should change, stay the same, as we look beyond this month?
Yeah. Thank you for that, Vamil. I have had lots of time to reflect on the last eight years, and really being able to bring to the forefront, I would say, a leading rare disease, and certainly within rare kidney disease, and the number of patients that we have been able to treat, o r give hope to is really something that is the greatest honor of my career. And I think as we look at, the board and I were looking at what is the ideal next leader for Travere's next chapter, Bradley fits the bill very, very well. He is a patient-focused leader. He is a known entity within rare disease, and has a proven ability to be able to bring medicines through the clinic, and also to commercialize successfully. I think from all of those aspects of we think what is important in Travere's next chapter, it is those.
I knew Bradley before this, so I can say that he is just a phenomenal person and also a leader, and I think is going to be very well received by internal and external stakeholders. The other aspect is, we are looking to continue to grow and build Travere, and his experience in business development and continue to make wise, disciplined investments as we grow is exactly what the board and I were looking for.
Okay. Great. Why don't we leave it there? Again, congratulations to you personally. Congrats to the Travere team. Thanks so much for joining us a gain, and we'll be watching for the continued progress.
Great. Thank you both.