All right. Welcome back, everyone. Next up, Eric Dube, CEO of Travere Therapeutics. Eric, I'll turn it over to you for an overview of the company, where things stand today, and then we'll get into it.
Okay, great. Thank you very much for hosting us. You can look on our website for forward-looking statements and some of the disclosures, since I will be making some of those. It's been an incredibly exciting year for us at Travere and for the rare communities that we serve. We have three priorities that we set out. The first is the ongoing launch of FILSPARI in IgA nephropathy. With the new patients that we've reached this year, we continue to see incredibly strong growth and support from the nephrology community, particularly in the recently published KDIGO guidelines that should drive a greater sense of urgency to treat these patients to ultimately avoid kidney failure.
The second priority is an sNDA with the FDA that's under review for a second indication for the treatment of another rare kidney disease, FSGS, that is even more rapidly progressing than IgA nephropathy and a very underserved rare disease community. We have a PDUFA date on January 13 for that decision with the FDA. The third opportunity that we have is our enzyme replacement therapy, pegtibatinase for the treatment of classical homocystinuria, or HCU. This also is a rare disease community that really doesn't have adequate treatment options. We have done a lot of work to increase the manufacturing scale. We paused enrollment in our phase three last year to be able to resolve some of those scale-up challenges that many companies face. We're on track. We're now manufacturing at that higher scale, and we're on track to reinitiate enrollment in our phase three next year.
We are well capitalized to be able to fully support all three of those opportunities.
Awesome. Exciting year ahead. Maybe we can start right into FSGS, main topic of investor discussion. Let's just start off on the regulatory side. Maybe you can give us a sense for how the process works with an sNDA. Like, when do you think the FDA would have their mid-cycle, late-cycle internally? When would you normally expect to go into labeling discussions, kind of those parameters?
Sure. For an sNDA, it is definitely more straightforward in terms of the interactions. There are less of them. Essentially, we submit, the file is accepted. We're given a PDUFA date. For us, it was January 13. There is not a mid-cycle or late-cycle meeting that we are involved in. That really is at the discretion of the agency. Around the time that we assume that they have their internal mid-cycle review, that's when we heard that the advisory committee that was planned was canceled. The reason they shared with us is that after further review of our file, they deemed that it was no longer necessary. There is not any official report that we get from late-cycle or mid-cycle. With regard to draft labeling and those discussions, that typically occurs around a month before the PDUFA date. We're still not quite at that point.
As you can imagine here, very soon we'll be going into a quiet period as we prepare for the PDUFA date.
That makes sense. When are you planning to go into a quiet period?
Very shortly. We have got a couple of conferences, obviously this one, and then thereafter we will be going quiet for the rest of the year.
All right. Makes sense. I guess looking ahead to the label, what's your expectation for how it'll read? Like, do you think there'll be a UPCR cutoff? You studied primary genetic patients. Like, do you think there'll be secondary on the label, like a broader statement? Like, what's your base case assumption?
Yeah. This is a request for full approval. We do not expect that there would be any cutoff for proteinuria. When we look at our clinical data as well as data for these patients, many of these patients have significantly elevated proteinuria to begin with. Even what would be considered less severe patients with FSGS, they still have abnormally high proteinuria, many of them in the nephrotic range above 3 g and certainly well above. We do not anticipate that there would be. If there is for some reason, we do not anticipate that that would be a challenge just given how proteinuric the patients who are diagnosed are. We have requested a broad indication statement for the treatment of FSGS. Just for background, there are a number of different types of FSGS: primary FSGS, which is considered more immune etiology.
There are different genotypes that can lead to FSGS. There's genetic forms of FSGS. As you mentioned, there's secondary FSGS, which can be secondary to other conditions. One of the most well-understood is diabetes or longstanding hypertension that can lead to scarring in the kidney, as well as many other different types of secondary causes. There is FSGS of unknown cause. This is a controversy within nephrology. The etiology, as well as the nomenclature here, fundamentally every patient with FSGS has a podocytopathy that progresses. There's nothing really effective for any of them that's approved at this point. We have requested a broad label to treat all of them, given the unmet need and the difficulty in really not just diagnosing FSGS, but the etiology of the disease that doesn't come with the biopsy.
We tried to study genetic and primary because that was what was, at least in the prior guidelines, really the focus of the need for innovation and to be able to manage variability within the phase three. If we do get a limited indication statement for genetic and for primary, that aligns with our estimates of the addressable population of around 30,000 patients that are diagnosed and really need something better. If we get a broad label, certainly that would be a broader set of patients that we'd be able to serve.
How much of an expansion is that for the secondary population?
For those patients that are diagnosed and still have a need for an additional treatment, that would go from 30,000 to anywhere between 40,000 and 50,000 is who we would see as addressable today.
Yeah, that makes sense. I guess let's start off on the provider side for adoption in the secondary patients. I mean, the feedback we picked up out of ASN was nephrologists are super excited about the secondary population, even despite not having much data there. Is that what you're hearing similarly? How do you think the adoption could be in those two segments, given the study population?
Yeah. We hear the same thing. I mean, first, we hear that it is difficult to identify the etiology, I mean, particularly for secondary, because you have to understand the clinical history of this patient. Again, the pathology report comes back and it says FSGS, not whether it's secondary or primary, et cetera. In many ways, the clinical course of these patients is consistent. I think that there is a real eagerness for something like FILSPARI to be treated broadly. If we think about, and perhaps some of the reason why we hear, particularly for physicians that attend ASN that are more academic, they know that there are other promising targets that are more focused on the immune side of the disease and could potentially be studied for primary.
I think they're logically thinking, well, then this makes sense to also be used in secondary because there likely won't be others in the pipeline.
Yeah, that makes sense. All right. On the payer side, I guess irrespective of what you get on the label, how are you expecting payers to manage the secondary population? What can they really do there?
I mean, that's also one of the challenges within FSGS because, again, there's no specific ICD-10 code for the type of FSGS. It's FSGS. You'd have to look at it by exclusion, whether they have other comorbidities that could lead to it. What's causative and the origin of the disease, it's really difficult for a payer. We have not picked up that payers are going to be looking at that. I think it's really focused on, is the patient diagnosed with FSGS? Do they have elevated proteinuria? Have they had a biopsy or genetic test to confirm that they have FSGS? I mean, these patients are incredibly sick. They progress rapidly. Even for those patients that are fortunate enough to have a transplant of a healthy kidney, over 50% of these patients recur in the healthy kidney.
It's a really devastating disease and for payers, a very costly one as well, especially if you think about the investment they make in a healthy kidney than being within potentially a matter of days or weeks having FSGS again. Anything that would help really does matter.
Yeah, that makes sense. That makes sense. I mean, what even would they hypothetically do if they wanted to restrict secondary access? Like, would it really be requesting a whole litany of EMR records, et cetera, doing all the exclusions? Or like, is there an easier way to do it?
Yeah, it's hard for me to speak to what a payer would do. I think it would have to be through medical exception. Again, these patients have diagnosed FSGS. They would have elevated proteinuria. They would have a biopsy. Even though we tried to exclude the patients in our phase two, phase three, we know that some of them with secondary were in or with unknown FSGS, just given the difficulty that physicians have in identifying the etiology.
Yeah. Awesome. All right. Dose in FSGS going up to 800 mg a day. From the trial, I think 90% of patients made it up to that dose.
That's right.
Can you see how many patients stayed on that dose over time?
You're correct. Over 90% of patients were able to achieve the target dose. We have a standard two-week up-titration schedule in our trials. We would assume that would be the same in the label. The overwhelming majority of patients stayed at that dose. Even if they down-titrated for tolerability, they could go back up. Most of the tolerability concerns, if there were, particularly around hypotension and dizziness, are typically self-limiting and resolve early. That's not something that we would see as an issue longer term.
Yeah. I mean, that's kind of a way of asking the next question, which is like, how many patients do you think will be on the 800 mg dose for FSGS? Do you think anyone will step down to the 400 mg kind of in the real world?
I think it's certainly possible. I think the experience that we have with IgA nephropathy in our patient support services to be able to help the physician, nurse, and the patient work through the titration schedule, because there is a two-week titration schedule in IgA nephropathy, we've seen great success in helping patients get to the target dose. Importantly, to stay there, the compliance and persistence with IgA nephropathy has been incredibly high. We'll make sure that we provide the same level of support and education for the FSGS patients and their providers as well.
All right, great. I think my last FSGS question. Have you picked up institutions that have waitlists of patients kind of ready to be put on drug? We started to come across some of that. I'm curious kind of what kind of warehousing you've seen commercially?
I’d say that there definitely is an eagerness for FILSPARI to be approved in FSGS. I think the unmet need is incredibly high, but there’s now a high level of awareness of the clinical data and also the importance of proteinuria as a prognostic sort of endpoint, given all the work that the community has done with PARASOL. I would say we definitely hear that there are a lot of physicians that are eager to prescribe. In terms of making a list of patients or warehousing, it’s hard for me to quantify what that is. Certainly, there may be some, but I’d say most importantly, there’s just a real eagerness and an urgency to want to prescribe quickly.
Awesome. All right. Moving on from FSGS, going back to IgA. I know you spoke about it a lot in the last earnings call, so I do not want to spend too much time on it. I guess just to kind of frame, revenue kind of outpacing PSFs, at least on a quarterly dynamic as we are working on it. Maybe you could just explain that dynamic in a little more detail.
Sure. I'd say that a lot of this really was over the year after getting full approval. If you look at the full approval that we got last September, we saw a clear step up in the new patient start forms, the number of patients that were prescribed. It does take time for those patients to get reimbursed. Payers then need to update their policy to reflect the broad label. For some patients, it may take a bit longer to be able to have those policies go through and to get that paid or reimbursed medicine. There was a period of time where that just took additional time. We've really worked through a lot of that. I'd say last quarter, you saw some of those dynamics working itself through where patients that were prescribed prior to last quarter then getting reimbursed.
I would say that's not a dynamic I would expect to see moving forward. It really should be much more of a homeostasis between new patients being prescribed and then getting reimbursed. There's still some period of time that it takes to work through the payer process, but that's really the main dynamic from last quarter.
Yeah, that's helpful. I guess to phrase it differently, there's a little bit of a gross net benefit you had, small one. Taking that out, this is a good base to work off with kind of a more adjusted and normalized kind of go forward cadence.
That's right. I mean, there will be some gross to net dynamics towards the end of the year with Medicare. Of course, with the insurance resets in quarter one, there will be those dynamics moving forward. In terms of the sort of underlying dynamics of getting patients from prescription to reimbursed, we should be on a steady course.
Perfect. All right. Thinking about the evolving landscape with BAFF/ APRILs, I think one of the investor questions is kind of more on the access side. Will payers pay for FILSPARI plus BAFF/ APRIL? What's your expectation on this? We look at FABHALTA policies as a precedent. What's your guys' current thoughts on this?
Yeah. I think that question requires me to answer sort of what payers will do as well as what nephrologists will do. I think we need to see how these are priced and how payers are going to establish policies there. We also can, and I think depending on what their price is, they're going to be perhaps more limited to the more severe patients. Also, nephrologists, the behavior is likely to start a new therapy in the most severe patients and then work. That's exactly what we've seen with the therapies that have been approved thus far. For those that are more immune targeted, like the B cell, like the complement, it's likely that that's going to be the case and then working. For us, none of that matters.
When we think about who the patients really that could benefit from FILSPARI, it's a patient that is inadequately controlled, not in complete remission, that is on an ACE inhibitor or an ARB. That's the overwhelming majority of these. We do expect that there will be combination. It's likely to be combination in the more severe patients to begin with. We will see how that dynamic plays out. For us, in terms of the opportunity to reach more patients, we really don't see the near-term dynamics really having a material impact. We also have seen payers approve combination of FILSPARI plus FABHALTA or TARPEYO. We would expect that that likely would occur with APRIL/BAFFs as well.
All right. Makes sense. Going over to peg ti and HCU for two and a half minutes. Maybe you could just kind of give us when HARMONY restarts, what's the cadence of enrollment going to be?
Yeah. We should expect to see a really nice uptake in enrollment for two reasons. One is when we started enrollment, before we ran into some manufacturing scale-up challenges, we really were monitoring and metering it because, one, we knew we were going to be working on this parallel scale-up in manufacturing. Also, this is a relatively new trial design where we have a pretty extensive run-in period to stabilize a patient's diet. That is new for a lot of these physicians that are not used to clinical trials. That no longer is the case. The second component is in parallel over the last year, we have been working on identifying patients, patients that are interested in the clinical trial, and which providers or institutions or clinical trial sites they are involved in. We know where these patients are. We will look to move very quickly.
Are you planning to do self-administration in this study?
We think that that's going to be the benefit and what most patients will want. That's definitely part of the program as well.
Makes sense. What about the protein tolerance sub-study? How exactly are you doing that? What's the protocol for increasing protein? How much details can you give us on that?
Yeah. I would say this is the thing that I'm most excited about with this program because it not only addresses what the regulators and what treating physicians want, which is to get control of a patient's homocysteine levels, which we know are toxic. For patients, they want to be able to eat as normal a diet as possible. They want to be able to introduce protein. We now have protocolized diet in this. We have a sub-study that for patients that are able to lower their homocysteine levels below certain thresholds, for example, 100 µM or 50, how much protein can we introduce while maintaining that control of homocysteine levels? That is the approach that we're taking. It really is, I think, a main reason why patients want to be in this study.
I think ultimately it could be a part of why we think pegtibatinase will become the new standard of care.
Makes sense. Do you have any bar for the amount of protein increase that you'd find clinically meaningful in this portion?
You know, it's going to vary patient by patient. That's going to be part of what we need to explore: how much protein does the patient want? How much protein can we introduce? That's definitely going to be part because when we talk to the treating physicians, they're doing it sort of based on feel and not empirically. We're actually going to have evidence to be. Very much.
Thanks.