Wonderful. All right, good morning, everyone. Welcome to TD Cowen's 44th Annual Healthcare Conference. We're going to be kicking off the first corporate panel session with, in my opinion, one of the more exciting corporate panels of the conference. We're going to be discussing IgAN, and we're very privileged to have the three companies up here with us, three high-quality companies in the space. My name's Tyler Van Buren, senior biotech analyst. I'm joined here by my colleagues, Richard Burrell, Tara Bancroft. On the panel with us, from Alpine, we have Mitch Gold, the executive chairman and CEO; from Travere, Eric Dube, president and CEO; and then also from Vera Therapeutics, Robert Brenner, the chief medical officer. So what we're going to do is we're going to start off with some general questions about the space, and then we'll go into some company-specific questions.
With the general questions, feel free to chime in, as you guys would like, before we go into company questions. But I'd just like to start by asking you guys how you think the IgAN treatment paradigm will evolve in the coming years, and how important rational combinations will be, and potentially what combinations you think might be most powerful. So whoever would like to kick it off.
I'm happy to start.
Sure.
So I think we're in a transformative era right now, and IgAN is dropping in, and I just, at the outset, I'm a nephrologist, and I can't tell you how excited I am, but here we are kicking off this conference. With over an hour on IgA nephrology, I think it's a phenomenal advance, and it's really a testimony to the leadership.
Can you guys hear him in the back?
No.
Yeah.
Is the mic working, or?
It says microphone.
We've got a green light.
There we go.
We're on? Okay.
Yeah. Anyway, it's, I think an exciting time in IgAN.
Oh, it's okay. Maybe volume higher?
Yeah, it's a bit high.
Okay.
Yes.
How are we now? No?
I'm getting a lot of feedback.
Shouldn't have heard the back of your.
Bob, are you?
I am one.
One.
Yeah. How are we doing?
A little better.
A little better? Maybe higher?
Yeah.
Any better now?
Yeah.
All right, so I was saying, I'm thrilled. I'm a nephrologist by training. The fact that we're starting off this conference with over an hour on IgAN and nephrology, I think, is a phenomenal situation. In terms of how treatment's evolving, I think we're really poised for a sea change. I think we are setting a new standard to think about disease modification in this disease for the first time. I think the prospect of turning off the production of immune complexes or modulating B cells is really a future cornerstone of therapy. I think, in addition to turning off immune complex generation, we want to have really thoughtful prescription for overall CKD hygiene, as I would call it. So I think there's room for multiple modes of intervention in the disease.
But the future for these patients has never been more promising than it has been in.
I would, I would echo that a little bit and just say, I think what we're going to see is you're going to see patients being treated earlier and earlier in their disease course now. What we know is that even patients with low levels of proteinuria, a high percentage of those patients go on to progress to end-stage renal disease and need transplant. So the fact that we now have a new set of therapeutic tools that physicians can use to treat these patients, I think you're going to see patients being treated much earlier on in the disease. And the goal here is to really prevent them from getting dialysis, prevent them from needing transplant time.
And Tyler, what I can add is really additional information on why we think combination is going to be a critical part of this transformation that we're seeing within IgAN and nephrology. If we think just simply that many of these patients go undetected in IgAN and nephrology until they have proteinuria or hematuria, it means that they have sufficient damage and loss of nephrons. And you know, the standard by which patients are diagnosed is through biopsy, which means they already have progressive disease and damage. By that point, you need to address essentially the overactivation and the damage in the kidney, as well as what would be very exciting in the future is to be able to address that upstream overactivation of the immune system.
I think by addressing that two-pronged approach is going to give patients, based on the current, journey that these patients are on, the best chance to be able to have that stable, disease course and hopefully be able to prevent, kidney failure in their lifetime. You know, many of these patients are in their 20s, 30s when they're diagnosed. And so it is a long time that we want to be able to, to keep their patients, their kidneys healthy.
So to Tyler's point about combination, are you seeing, as the paradigm evolves, either sequencing or stratification of patients appropriate for a first line, a second line? You know, we go to ERA, and we hear about chronic lesions. We hear about acute lesions. How are doctors starting to bucket patients?
Maybe I can start, given that we have our medicine approved, FILSPARI, and we can speak to this. This is really a question with not a lot of evidence to date. We talk about the ability to be able to go first line. Unfortunately, there is not much in the way of evidence to be able to support first line. In fact, the only study that's being done is one with FILSPARI, where we look at an incident population of treatment-naive patients. And we do see that those patients actually respond very well with stabilization of eGFR. Right now, we've got data out to 36 weeks. And so there, I think, is a real promise for these patients that if we are able to provide medicines that are designed and developed specifically for IgAN and nephrology, they will have a better prospect.
What we're seeing now in the treatment of patients is that there is an eagerness from nephrologists to use new combinations. The SGLT2s now, even though they weren't studied specifically in IgAN and nephrology, they're subgroups of larger studies. There is a view that they are renal protective. And many of these patients are on SGLT2s. But we know that's not enough because it's not addressing the immune overactivation, and it's not addressing the overactivation that's going on in the kidney. And so we believe, and what we're hearing from top KOLs is that there has to be an increase. But I don't think we have enough data yet to look at segments of patients based on phenotype of that, other than patients that may be at greatest risk of progression, those that have crescents in their biopsy.
But I think the data thus far is not mature enough to be able to really segment these patients, which goes to, I think, the view that there's going to be a foundational therapy and an upstream therapy that's going to be needed for most patients.
I would agree with that as well. I think what you'll see is, physicians wanting to use disease-modifying treatments early on as frontline treatment in the disease. Having a B-cell modulator that could really modify the disease outcomes early on and then adding on other treatments downstream, we think, will make a lot of sense from the patient's perspective.
How has FDA's stance on developing drugs for IgAN changed over the years? I mean, the cardiorenal, especially renal, has been notorious.
Eric did that.
In a bad way. You know, specifically, has the agency's opinion on biomarkers and accelerated approval changed, improved, especially in regard to UPCR?
Yeah. I mean, I think, you know, certainly there has been a view that cardiorenal has been conservative. I would argue that that is actually a reflection of how nephrologists think, that it is evidence-based, and that you've got to have data on outcomes in order for there to be new therapies. I think this is an incredible story that we're seeing play out in the last couple of years and really the plethora of development programs in IgAN and nephrology because FDA listened to the patient community to say, you know, using off-label steroids, ACEs, and ARBs are not enough. And over the last few years, with the KHI public-private partnership, FDA has accepted that proteinuria can be approvable for accelerated approval.
We now have two medicines that are approved, in that and one with full approval, hopefully, a second one, by the end of this year. So it's certainly evolving. One other aspect that I can point to of FDA continuing to evolve their thinking as more evidence evolves is, you know, we presented the two-year confirmatory data from our PROTECT trial. And the FDA requested that we use a slope analysis of eGFR as the confirmatory long-term endpoint. We believe that slope is a very difficult measure because it essentially assumes a lot of information in what we know is a variable time course in any patient with the measure of eGFR. And at ASN, FDA said that they are moving away from the measure of slope analysis for that very reason. eGFR still is going to be very critical, we believe.
We're excited to see proteinuria because it means that you can, you know, measure the effectiveness of these medicines much earlier. So we do believe, and I, I believe that, FDA has continued to evolve as the literature and as the evidence evolves. But I think that eGFR and proteinuria will become will be, pillars in this, regulatory pathway for the foreseeable future.
Any new biomarkers bubbling up beyond UPCR?
I don't believe that we can certainly defer to Dr. Brenner. But we've not seen anything that is predictive of outcomes, which is the standard by which FDA is looking at the adopting a surrogate endpoint, which is why proteinuria now is the standard.
There's some history here. We know that in the past, drugs that were developed for different forms of kidney disease were looked at, initially for a composite endpoint of doubling the serum creatinine or time to end-stage kidney disease. By and large, those trials were done in diabetic and non-diabetic forms of progressive kidney disease. But they enrolled subjects who had quite low GFR at the time that they entered the trial. So they had GFRs in the 40 mL/min range. In contrast, in IgAN and nephrology, we see many patients being enrolled with greater kidney function at baseline, GFRs in the 65 or higher mL/min range. That means if you were waiting for time to ESRD, you're going to be waiting many, many years. So it becomes untenable. Credit to the Kidney Health Initiative, the patient advocates, companies like Ericsson.
They've had the conversations with the FDA. Now we live in a situation where there is a benchmark for what requirements are for approval, certainly in the U.S. That's great for all sponsors. I think when we think about IgAN and nephrology, as we think about regulators and payers and also prescribers, I think we're thinking about a quartet of findings, right? We're thinking about generation of immune complexes, which is driving the disease process in the first place. We think about evidence of active nephritis, which we can measure by looking at blood in the urine or hematuria. And then we can look at proteinuria. And we can look at, most importantly, GFR. So I think all of those are relevant. Whether they're essential for every regulatory audience, I think, is less important. But they're part of telling the integrated story of disease modification.
Okay. How about a general question for the development space? So can you talk about the relative contribution of BAFF and APRIL for B-cell modulators? And how might BAFF add improvements on top of anti-APRIL therapy?
Yeah. Maybe I'll start, and then you can, you can add.
So I would say, you know, BAFF and APRIL have overlapping but non-redundant roles. And, you know, BAFF's probably the most validated of the two targets. Obviously, we have Benlysta that's approved there. So it's approved in lupus and lupus nephritis. But APRIL has emerging data that looks very encouraging. The way we look at it, and I don't know if the team from Vera looks at it the same way, but we look at it as APRIL has an effect early on. So it affects more late-stage B-cell development, plasmablasts, and plasma cells. So you see rapid reductions in the antibody reduction. You probably see rapid proteinuria reductions as well. But you need BAFF for kind of long-term treatment outcomes. So that's why when you see kind of the long-term follow-up that Vera presented a couple of months ago is very encouraging on long-term eGFR outcomes.
So you need to cover both. COVID-TAC is said to have been designed from its initiation to be a very potent both BAFF and APRIL antibodies. So we're the most potent on the APRIL axis. We're as potent as the anti-APRIL antibodies. And we're even more potent than Benlysta on the BAFF axis. And because of that potency, we're able to achieve a once-a-month dosing regimen.
Okay. Well, I guess that was, that was a good intro to povetacicept, as said. But can you review, highlight takeaways, your favorite parts of your data from ASN in November? And what gives you the most confidence in these early findings?
Well, I, I think overall, the space is becoming incredibly well understood. And so we have good benchmarks to really compare ourselves against. So obviously, UPCR reductions is becoming very important. And stabilization of eGFR now, I think, is the standard. So you have to see stabilization of eGFR. At ASN in November, what we presented was we saw, at six months, we saw about a 53.5% reduction in UPCR, which was the deepest UPCR reductions seen at that time point. And we saw stabilization of eGFR. So that was very encouraging, that given that atacicept is said to be only using 80 mg of protein a month. So it's a very low amount of protein administered on a monthly basis. We've now obviously had a number of more patients enrolled. So we've enrolled the 80 mg cohort. Our 240 mg cohort is continuing to enroll.
I can tell you that that's enrollment has gone incredibly well. We have more patients at 240 now than we have at 80. We look forward to presenting that data later on this year.
For that update, can you give us any hint at what conference it might be at or even actually just outline which kidney conferences are happening in the first year to?
Yeah.
To better understand that?
Two things. So one, there's two main renal conferences happening in the first half of the year. We've guided that. We'll give an update in the first half of the year.
Yep.
The two main ones are WCN in Buenos Aires and then ASN as well. So, I'm sorry, ERA. So, ERA in Stockholm. So we'll be at both those conferences. And we look forward to sharing updated data from the PROTECT there. What you should expect is that we'll have longer-term follow-up data from our 80 mg cohort, not just at six months, but we'll have nine-month data as well to share. And we'll also share our first look at 240 mg as well at those conferences. So it'll be a substantial update for the company.
Okay. And if you're following patients after 24 weeks, to what extent do you think you could see improvements at later time points?
Well, what we've said publicly before earlier on this year is that, you know, we've had additional patients come through. And we're not, you know, we're not seeing any degradation in the data. So we're very confident that, you know, I think one of the most appealing elements of COVID that I didn't mention earlier was that we saw a very high remission rate. So we set up a stringent set of criteria. We said that patients had to have their UPCR at less than 0.5 g per gram, a 50% reduction in their UPCR from baseline. And they had to have a stable eGFR. And when we used those three sets of criteria, 80% of our nine patients met that remission criteria. And so that's a criteria that we want to continue to follow.
This concept of remission is one that I think is going to continue to come into play in the IgAN and nephrology space and one that I think we need to really strive for as a field. And because we're seeing that remission rate, we're seeing our patients continue to have durability in their proteinuria reductions over time.
All right. Eric, let's turn to you. So with FILSPARI, in Q4, you guys put up a great number, $15 million, roughly 50% of first-year launch sales, just like you guys roughly guided to. However, patient start forms grew 7% quarter-over-quarter. So what can we expect from FILSPARI throughout 2024? And how do you plan to continue to grow the franchise quarter-over-quarter?
Yeah. Well, I think we were very pleased with the first year of, of launch. We were approved under accelerated approval in mid-February of last year. This is the first rare kidney launch where we've seen quarter-over-quarter growth in the first year of launch, which I think reflects both the profile of FILSPARI as well as the high level of unmet need within the IgAN and nephrology community. We certainly expect to see steady growth this year in terms of demand and a real inflection in that growth in demand or patient start forms later this year when we expect to receive full approval, which should lead to a broader indication statement, certainly reflective of at least the population that we've studied.
but also, that's around the time that we would expect the KDIGO guidelines, these are the global guidelines for kidney disease, specifically within IgAN and nephrology, to be updated, where we expect both the inclusion of FILSPARI as a new foundational therapy, essentially replacing the roles that ACEs and ARBs have played off-label in the treatment of these diseases, but also to be able to lower the threshold target for UPC, really aiming for even better proteinuria. And that's largely based on an analysis that was published that we helped to support in really understanding this disease better. Mitchell mentioned this, that you know, even patients that are above 0.5 grams of proteinuria have about a 25%-30% risk of entering kidney failure within 10 years. So we think there's going to be a greater sense of urgency that comes.
So, you know, by the end of this year, once those, you know, we get full approval and KDIGO is updated, that's where we expect to see a broader addressable population and a further inflection in our growth rate. But with regard to revenues this year, we expect to see even stronger growth than demand because we have a very strong base of patients that are highly adherent to their therapy. And we continue to pull through and, you know, expect payer coverage to get even stronger as we have further data.
So on that topic, what do you believe, or what is the ultimate peak sales opportunity for FILSPARI and, upon potential approval later in the year, if FILSPARI's label was to be broadened to include a labeled UPCR below 1.5 g, how much would that expand the addressable patient population?
Sure. Well, I'd say, you know, speaking of the indication statement first, we would expect that we would have an indication that statement that removes proteinuria levels. I think this is similar to what we see with TARPEYO, where it's essentially the treatment of IgA nephropathy for patients at risk of progression, which would substantially increase the number of patients eligible for FILSPARI. But also, we believe that, you know, the addressable population for us currently is about 30-50,000 patients in the U.S. That would grow to over 70,000 based on the broader population, broader indication, and the KDIGO guidelines that I mentioned. This is clearly a larger prevalence in rare disease. And with those numbers, we believe that this is a multi-billion-dollar, potentially $6-$10 billion opportunity as a market size.
We've talked about FILSPARI peak being over $1 billion in IgAN alone.
Dr. Brenner may want to come on this as well. But in some ways, I look at IgAN similar to other indications, where they didn't have the right toolkit. But as tools become available, more patients become identified. So I think this is a much bigger market than any of us really anticipate. And that's really indicative of how fast the clinical trials are enrolling there. I mean, you see how fast Vera enrolled their Phase III trial, how fast it's enrolling, and how fast it's enrolling with sibeprenlimab. This is and we're seeing patients flowing into our trials as well. So I think, this is a much bigger patient population than we currently anticipate.
Rob, let's, Dr. Brenner, let's start with the highlights of your top-line 36-week Phase II ORIGIN data from ERA last year and the more recent 72-week, open-label, positive follow-up that you presented mid-January. You showed atacicept at 36 and 72 weeks led to eGFR stability and static separation from placebo at 36 weeks and reductions in proteinuria, hematuria, Gd-IgA1 through that 72-week time point. Moving forward, do you expect this continued stability through 96 weeks and even beyond? I guess, you know, none of the therapies that we've discussed today actually bring that Gd-IgA1 or that complex down to, like, absolutely zero. So is there a chance that even that tiny amount over the lifetime of a patient could degrade eGFR from that stability that you've flatlined in your data?
Yeah. Thank you for the question. So I think it's important to recognize that IgAN in nephrology is a B-cell disorder with a kidney pathology. So what is that B-cell disorder, right? So there is the production of this galactose-deficient IgA or IgA that doesn't have the normal complement of sugar that's coating it. And that exposes an autoantigen, which IgG or IgA can bind to. And what's so interesting about this disease is both the autoantigen and the autoantibody are produced by B cells and plasma cells, which we can modulate with a dual BAFF and APRIL inhibitor like atacicept. So we all have a certain amount of Gd-IgA1. All of us in this room have it. What we don't have is a pathologic amount of Gd-IgA1. And we're not forming any complexes.
In our 36-week randomized placebo-controlled Phase IIb trial, we showed that we had about a 60%-65% reduction in Gd-IgA1. Now, you could ask the question, what's the amount of Gd-IgA1 reduction that's ideal? I think the best way to answer that is to look at the full complement of results and work backwards. So no one would have been able to say, "If I can get to 50% or 60% or 70% or 80% or maybe 100% reduction of Gd-IgA1, then I'm going to have the best outcomes." What we can say is, working backwards, after 72 weeks of following patients on 150 mg of atacicept self-administered at home, we have stability in GFR. We've transformed them from a phenotype, a progressive kidney disease with IgA, to one where their GFR profile looks like the general population.
That's associated with about a 50% reduction in urine protein excretion over those 72 weeks. It's associated with resolution of hematuria or evidence of active nephritis in over 80% of subjects and a 65% reduction in Gd-IgA1. So that becomes a quartet that can define what disease modification looks like. So my expectation is we'll continue to see in patients who are treated that they will have low formation of immune complexes. They won't have evidence of active nephritis. Their proteinuria will stay low. And their GFR will continue to reflect more of a general population phenotype of about 1 ml/min/year.
Is the technology there to quantify the complex? Because that's sort of halfway in between.
So the Gd-IgA1 is a great measure that can inform on immune complex burden because it's the autoantigen. But yes, we could also look at, likely, immune complexes themselves. Now, where would we see immune complexes? We see them on kidney biopsy. So patients are referred by nephrologists to themselves for this biopsy or with a radiologist. And when we stain the sections from the biopsy, we see the evidence of immune complex deposition. So that's one place where we see it. And one of the things that we're excited about at Vera is, over time, looking at follow-up biopsies in patients who are early diagnosed with IgAN and nephrology and show that when they're on drug for a year, two years, etc., what does the repeat biopsy demonstrate in terms of resolution of some of the pathology?
Do we see evidence of less immune complex deposition in the kidney? I think they'll be very exciting.
Got it. So far, you're the only sponsor to show reductions in hematuria in relation to your data. You referred to it as active nephritis. Can you talk more about that clinical significance of reducing hematuria? What aspect of the active nephritis are you talking about? Are we going to see more discussion in the landscape going forward?
Well, so first, I think we will see more discussion about this. I expect that there'll be more while hematuria will be quantified. It is part of the disease. Many patients are presenting for the first time with a urine dipstick that's positive for blood in the urine or hematuria for other reasons. They may be a college athlete. They may be going and starting a new job, getting a physical exam. The dipstick comes back positive for blood in the urine. They eventually get referred to a nephrologist. They eventually get a kidney biopsy. So we know that IgAN and nephrology has a component of the disease that's characterized by active inflammation in the glomeruli, which results in blood in the urine, microscopic hematuria. You can look under a microscope and see dysmorphic red blood cells.
Or you can use a simple dipstick and quantify the amount of blood that's in the urine. So it's a common thing. We're now at a point where there are publications that associate poor outcomes in patients with IgAN and nephrology who have hematuria, just like patients who have proteinuria and just like patients who have a more rapid decline in GFR. So I think it's a component of the story, and it adds to the richness of what a disease-modifying proteinuria as well as proteinuria and stabilized GFR.
So Mitch, back to you. Kind of want to stay on the data that are coming up. So can you talk about what you saw preclinically and in healthy volunteers that led you to select the 240 mg dose, general expectations that we can expect there, and what you would need to see to take that forward instead of 80 mg?
Yeah. So povetacicept was designed from its onset. So it was a molecule that we engineered in-house. It was developed at Alpine. So we don't have any downstream royalties or milestones that we own any third parties. And it was designed to bind the APRIL and BAFF very poorly. And so because of that, in our Healthy Volunteer trial, as you mentioned, we dose all the way up to 960 mg in a single dose. And when we looked at our dose escalation, what we saw was that at 80 mg, we covered our targets for about three weeks. And then we came off a little bit. At 240 mg, we covered the targets fully.
So when you look at our 80 mg data from our RUBY-3 study in IgAN, we can see there is even at our 80 mg dose, we're seeing this deep reduction in proteinuria, stabilization of eGFR, and a higher remission rate. And the Gd-IgA1 level dropped consistent with others in the space down about 60%-65%. So we know that at 80 mg, we're having the treatment effect that we want in IgAN. And when that data was shared at ASN in November, the KOLs came to us very vehemently and said, "You have the drug. You got to push this forward into Phase III as quickly as possible." So we're pushing that forward into a Phase III study in the second half of this year, but we're also studying 240 mg in the RUBY-3 cohort.
So what 240 would need to show would be a substantial improvement in UPCR reductions, or a higher remission rate. You know, we're already at a level that we think positions us as a best-in-class program at 53.5% reductions at six months and stabilization of eGFR. It's obviously something you want to continue to follow out. Nine-month UPCR reductions is the approval endpoint for accelerated approval. So 240 would need to be dramatically better than our 80 mg data for us to shift to that. At the 80 mg level, that's very appealing from a cost of goods perspective to us. That's 80 mg of protein a month compared to 600 mg or 1 gram given for other programs currently in development. At commercial launch, it'll be given through an autoinjector. The injected volume will be under a half a mL.
Okay. How is safety been so far? Can you describe in more detail first what, in general, you look out for with this type of therapy and what you saw at ASN?
I mean, I think this is one of the, you know, elements of the class that's been so exciting. So historically, there was an overhang with the, you know, the wild-type TACIs in this class. And that's, I think that was more trial conduct than associated with the drug. So whether you're looking at, you know, the wild-type TACIs that have been put in development, they're, these are overall very safe. And povetacicept is safe to us. It was very safe. When you look at our data from RUBY-3, we're not seeing any high-grade infections. We're not seeing any incidence of hypogammaglobulinemia. We're not seeing any injection site reactions. So overall, povetacicept is safe. But that's also true of the class as a whole.
Okay. What, what do KOLs say is an acceptable level of hypogammaglobulinemia?
I think typically, they're looking at, you know, three grams per liter is typically the number that they're looking at. But it's not just that. I don't think you can look at that just in its own box. You have to look at, are you seeing any higher incidence of infections or other issues with immunosuppression? We're not seeing that. Povetacicept is safe. And we haven't seen reports of the wild-type TAC reporting out issues with those either.
Eric, back to you. Earlier, you mentioned that you guys expect to full approval later in the year for FILSPARI. But can you just reiterate your confidence in that based upon the PROTECT data that we saw in the fall? And, secondarily to that, can you talk about the REMS submission and what you think the likelihood is of getting the black box warning and the REMS program either removed or modified?
Certainly. We have met with the FDA when we had the full two-year data, as a pre-NDA meeting. The first answer to the questions from FDA was, "We agree with your plans to submit this, these data for full approval." In looking at the two-year data, although in one measure of eGFR, the total slope, which historically had been what FDA was looking for, we nominally missed on significance. All other measures of eGFR showed superiority versus maximally dosed irbesartan. I think FDA and certainly the nephrology field recognizes both the rigor of the trial design and the rigor of the trial conduct, but also the consistency of benefit.
When you look at other measures that actually of eGFR that took into account that there was a discordance in the number of patients on irbesartan that had to be rescued on steroid therapy, for example, or stopped therapy prematurely because the therapy wasn't working for them, all of those things certainly further benefit FILSPARI in the analysis, as well as the very consistent reduction in proteinuria that you see over time. I think even equally encouragingly was the two-year safety data. We saw, you know, no change in the safety profile, including no cases of liver damage. And the rates of AST, ALT were comparable to irbesartan, a class of medicines that has been used for decades. And in fact, the rates were lower with sparsentan over two years.
And so we believe it gives us a strong foundation, not just to submit for full approval, which we're on track to, to submit this quarter, but also in requesting a discussion about the REMS. FDA, when they indicated late in our review for accelerated approval that they would put a REMS, for, liver monitoring, that they also are open to reevaluating that need with additional data, because it was under accelerated approval. And in their eyes, you know, the data, the safety data package, as well as full benefit, hadn't been elucidated. We now have that. So we would look to, at a minimum, request even reducing the frequency of liver monitoring, to, you know, perhaps every three months rather than in the first year every month, which, you know, for many patients, they actually say that it's a benefit.
We have incredibly high compliance because they feel that connection. Also, the additional testing and connection with their physician shows that FILSPARI has a very profound reduction in proteinuria within a matter of weeks to months, which for a patient, when they feel like they've progressed since they've been diagnosed, is, in their words, life-changing to be able to see an improvement so profound within a matter of months. So we think that it's not been a significant barrier for patients that have been on the therapy. But we do believe that for particularly, you know, people that are working multiple jobs and see once a month as a difficulty, even moving it to every three months should help in improving the demand for FILSPARI.
Yeah. Great. Now, at the end of the month, we expect a CHMP opinion for FILSPARI. So what do you think is the probability that that is positive? And how do you and your partner, CSL Vifor, think about the opportunity for FILSPARI in Europe compared to the U.S.?
Certainly. Well, if we talk about first the opportunity, there are as many, if not more, patients with IgAN and nephrology in Europe. And so the addressable population, as well as the unmet need there is just as high, if not higher, than in the U.S. So it's an incredible opportunity, which is why we partnered with CSL Vifor, one of the leading renal companies within Europe. And we believe that will be very important and not just regulatory, but also, more importantly, reimbursement and HTA engagements. We have recently announced that we received CHMP positive opinion.
We were very pleased to not see not just that, but that the indication will be for patients that are above 1 g/g , which really, I think, are one gram per day, which is broader than what another therapy in a space received under conditional marketing authorization and truly reflects the consistency of benefit that we've seen in our clinical program. So we're on track in the next two months to receive full approval or to receive conditional marketing authorization, the actual approval, in Europe. We're confident that CSL Vifor has a great plan for reimbursement and launch.
Tyler, I'll just add, I mean, just I'll add on to that a little bit, which is, you know, the concept of reducing proteinuria early and, in fact, that patients are tracking it is really important. Patients want to see their UPCRs come down. If you look at the RADAR Registry, what Peter Barrett reported there was that for every 10% reduction in UPCR over either 12 or 24 months is a commensurate delay in your progression to end-stage renal disease and transplant. Early proteinuria reductions and deeper proteinuria reductions have benefits in clinical outcomes. That's from the RADAR Registry.
Great.
So, Rob, you've, you've got this very rich data set right now, hundreds of patients, three doses, 36 weeks, 72 weeks, 96 weeks is coming up. I'm getting a lot of questions about further subgroup analysis that we might get from forward data presentations, especially questions on how those SGLT2 background patients are doing. You guys have more than anybody else. You've got the deepest data set on how this field is going to evolve, how those Phase IIIs that everybody's running, including yourself, how they might, their outcomes might be affected by rising SGLT2 background.
Yeah. So first, on the totality of the data, I do think it's important to take a step back and to remind ourselves that the Phase II program for atacicept is safe. Really, so far, it's the first placebo-controlled clinical program that's used a dual BAFF and APRIL B-cell modulator. So we can speak confidently about the safety profile because we have the placebo cohort to compare. I think, I think that's important. In terms of SGLT2 inhibitor use, we saw about a 14% or 15% use of SGLT2 inhibitors in the Phase IIb trial. Today, as we're enrolling in Phase III, I expect we'll see more, because the general use of SGLT2 inhibitors has increased.
What the Vera team used, as a paradigm to get into the trial is you had to be on a stable dose of an SGLT2, just like you had to be on a stable dose of a RAAS inhibitor because those drugs can have a short-term impact on proteinuria, in particular. And given that that's the key endpoint, we'd want to make sure you have fidelity to look at the intervention, when you're doing those measurements. And so by having stability in those doses, you at least control for concomitant adjustment that could impact the proteinuria. That's another reason why having a placebo control is really helpful. So we've used that. We will continue to use that paradigm in Phase III. We'll require that patients are on stable doses. But we recognize that those drugs are being used.
So it's important to have kind of a representation of what's going on in clinical practice in our program. I'm confident that the design of the Phase III will allow for that and allow us to have really full confidence in our ability to determine the GFR and proteinuria measures that are important for approval.
So those 15% of patients, are they going to inform what you expect out of the Phase III, ORIGIN-3? And, and how is, enrollment and site activation on ORIGIN-3 going?
I think it's important to us to have a profile of participants in the trial that generally reflects the population at large. So we'll see an expansion in SGLT2 inhibitor use, part and parcel with the expansion of the drugs being used in clinical practice. That's appropriate. In terms of your second question, Roland.
How was ORIGIN-3?
Oh, enrollment.
Site activation.
Enrollment's going great. Our team had, you know, all kinds of estimates of what site activation and screening and, and enrollment by site, by week, by month is going to look like. We're tracking exactly to that, if not a little ahead. We're, we're very pleased. It's a global trial. We think it's representative of the disease burden across the globe. That was important for regulators. I think, you know, we're on track to, to complete the enrollment, for the first 200 subjects, as we shared, previously.
Framing expectations, should we expect the same target that you guys put out for ORIGIN-2, that 30% placebo-adjusted UPCR?
Well, we showed at the 72 weeks, we had a nearly a 50% reduction in UPCR, in subjects who had either been on drug for the full period of time, the full nine or full 18 months, or for those who had nine months after they switched from placebo. So I think it's in that 40%-50% range, which is what we'll continue to see. I think we'll continue to see stability in eGFR.
Can I just add something to your first question, which I really resonates with what Rob said? I think in terms of some of the increases in SGLT2 use for the real, I'd say, upgrade that we're seeing away from off-label ACEs and ARBs, which we know are insufficient. I mean, despite the RADAR database was essentially all patients on ACEs and ARBs. And yet, all of them are likely to progress to kidney failure in their lifetime. What we've been dealing with in treating patients with IgA nephropathy is with insufficient tools. And so what I'm really excited about for the future for these patients is to have not only the potential for disease-modifying therapies that address the overactivation of the immune system, and the deposition of IgA, but actually an improvement in the foundational therapies that we're seeing.
So the renal protection that we're seeing with SGLT2s is an important component of it, but fundamentally isn't going to address either the activation of Gd-IgA1 or the overactivation in the kidney that has been the target for ACEs and ARBs for so long. So I think going back to the first question, what I'm most excited about for people living with IgA is that there will be tools to be able to address and the courage of companies to be able to include the standard of care as foundational therapy while you add in or whatever point in the disease progress you have this upstream targeting. So I don't think that there's going to be a curative, but I don't think that patients need that given what we see on the near-term horizon.
Can I ask you one follow-up question to that?
Sure.
It's none of your drugs, but where do you think complement inhibitors or complement drugs will fit into this?
I think it's a question that the nephrology community is asking themselves. I think with what we've seen in the profile of these two companies, as well as what we've seen in the superiority of FILSPARI as a foundational therapy, gives an incredible outlook for these patients. I think we've got to see the evidence of where we'll complement, but certainly, Rob, you can.
Yeah. I mean, I'll give you my personal view. And we shared this at our R&D day back in January. I think if we are able to, if we understand the pathophysiology of the disease, right, it's an immune complex-mediated disease. And we know with dual BAFF/APRIL B-cell modulation with atacicept is safe, we can decrease immune complexes. We evaporate the hematuria. You can now say, why would you need the blunt instrument that steroids or complement inhibitors represent for overactive inflammation in the glomerulus? If you can prevent that inflammation from occurring in the first place because you don't get the deposition of immune complexes, you don't need those. Now, it doesn't mean we don't need them in kidney disease in general. And it doesn't mean that some subjects might have a situation where it's relevant.
But I think the window is rapidly closing for where those drugs make sense in an era where we have true disease-modifying IgAN therapies. And that's what's so attractive about the data that's emerging is it allows us to think about a lucid kind of evidence-based approach to the disease because we understand the pathophysiology, we understand the mechanism of action. I would agree with that. And I think that's what's getting physicians so excited about using disease-modifying drugs early on in the treatment course where they don't have to use these blunt instruments. They can use more elegant tools going forward.
Great. I think we are at time now. Thank you. Thank you.
No, I think it goes until 10:20.
We have 10 more minutes. Sorry.
20 minutes. All right. Just kidding.
Yep. Sorry.
Can I ask, you know, while we're on this topic, Mitch, can you discuss your upcoming pivotal trial, what the design could look like, sample size, what control, and also in keeping with that previous discussion, any thoughts on prior background SGLT2 or RAAS?
Yeah. So obviously, we're going to allow, you know, stable background therapy entering the trial. But it'll be, it won't, we're not going to reinvent the wheel here. The trial for what we're calling, it's going to be called the Rainier Phase III Study in IgAN. That'll be size similar to other Phase III trials that are currently ongoing in development. We'll launch that trial in the second half of this year. And, we're very excited to get it up and going. We're getting very strong investigator enthusiasm for that trial.
Okay. Are there any manufacturing considerations that need to be worked out ahead of that?
No.
Like how easy or hard?
We have our commercial formulation in hand, as I mentioned earlier. At launch, we'll be delivering povetacicept in a single autoinjector. It'll most likely be an 80 mg dose unless the 240 mg data that is continuing to mature looks dramatically better than that. But currently, we're anticipating it will be an 80 mg dose. That'll be about a half, just under a half ml inject volume.
Okay. Do you want to go?
Yep. Eric, I'll talk about the underwhelming outcomes from ACE/ARB therapy and RADAR. I want to ask you about the SGLT2 combination and frontline data later in the year. So what should expectations for both of those updates be? And how might you continue on developing in those areas if the data is positive? Sure. Well, certainly, we heard early on from nephrologists that they were eager to understand how FILSPARI could work with SGLT2s. And so we have two different trials to be able to support the different sequencing. We know that many patients actually come through their primary care to a nephrologist, already on an SGLT2. And so we felt it was prudent to be able to look at what is the additional benefit of adding FILSPARI to a patient on stable SGLT2? We'll be able to provide data from that later this year, likely at ASN.
We also have data that is being collected from our PROTECT Open-Label study, looking at patients that have benefited from FILSPARI, on a stable dose, and then what the incremental benefit would be from SGLT2s. I think most importantly, the question that we're hearing from nephrologists is, what is the safety? We want to understand that it's safe to combine. I think it's important to reflect that the goals that nephrologists have of using these two classes of medicines are very different. For FILSPARI, it's about getting a profound and sustained reduction of proteinuria and to really replace that foundational role that ACEs and ARBs have played. With SGLT2s, there's not really an expectation that there's going to be a profound reduction of proteinuria. It's really modest.
But it really is in providing that longer-term renal protection that we've seen from the outcome studies in broader CKD that I think have attracted some nephrologists, although it's not, it's not clear-cut. There's still debate about where to use it, given that it was really a sub-study of a broader study and to be able to look at what's the right patient type. So that remains to be seen. With regard to FILSPARI and line of therapy, certainly, we expect that the majority of patients that will be available, for any new medicine are going to be patients that are already on an ACE or an ARB. In fact, most patients come through referral on an ACE or an ARB. But we are, taking a step with our SPARTAN study, which has been, conducted in treatment-naïve patients.
What we've been able to see is an 80% reduction in proteinuria at 36 weeks, a stabilization of eGFR, and the majority of these patients, two-thirds of them, in complete remission of proteinuria. So a very profound profile. This is a small study. I, I want to caveat. It's a small study. It's a repeat biopsy study. So we want to look not just at what's going on functionally at some of these measures, but also structurally. These studies are incredibly difficult to conduct, to be able to ask a patient to do what was one of the most painful procedures and scary procedures of a biopsy, to do that twice. So these will be small numbers, but we are very excited to be able to provide what is, what is currently the only trial in, in first-line therapy. We're doing this more to understand the mechanism.
We don't expect that there is going to be a sea change in how patients are diagnosed in the U.S. because most patients are diagnosed when they have hematuria or proteinuria on routine lab. That means there's already deposition in the kidney. There's already damage going on. And they need both an upstream immune-mediated targeted therapy as well as a foundational therapy that addresses the overactivation in the kidney. So while it would be really exciting to imagine a world where patients are diagnosed prior to that damage occurring, I think our health system can't even screen for urine protein for chronic kidney disease, given that there are tens of thousands of patients in the U.S. with chronic kidney disease. I don't see that practically occurring in a rare disease.
That said, it's really exciting to see that we'll be able to have evidence from our company as well as others to see what could be done if we are able to intervene earlier.
Okay. That's helpful. And earlier, you talked about the FDA evolving their thinking, in the area of IgAN. And obviously, FSGS is somewhat related. So can you just talk about the potential for the FDA to evolve their thinking in that area as we look out over the course of the next year?
Sure. This is, this is one where I am incredibly optimistic, because this FSGS, if we talk about the unmet need in IgAN, FSGS is an even more devastating disease. These are patients that really have very few options, nothing approved for them. And the progression, of this disease is even more rapid. Most patients are diagnosed when they have nephrotic range, proteinuria.
And so I think the FDA and certainly the nephrology community recognizes this incredibly high unmet need. We conducted the only pivotal trial in FSGS and reported that last year. And the proteinuria data, very consistent in a 50% reduction, and superiority over what is currently the standard of care ACEs and ARBs. We did not show a significant benefit in eGFR. This is a disease that is relapsing, remitting. And so eGFR in an average patient is variable to begin with. So to be able to show a signal from the noise in a clinical trial on eGFR is incredibly challenging. Recently, the FDA reinitiated a public-private partnership called Parasol, which works with the top thought leaders in FSGS as well as the patient advocacy community, NephCure, to redefine what would be a pathway in FSGS. And they've already acknowledged that eGFR is not the right endpoint.
Now, I think, you know, certainly, you know, we helped to contribute that, that in a very rigorously, rigorously designed trial. What we're now working with is to understand how this, team, the Parasol group, will look at other measures, for regulatory pathway, likely proteinuria, given that that is the hallmark measure, in this disease. Those, that group is going to be meeting this summer in June and will be reporting out based on reanalysis of existing registry data. What might be a measure of proteinuria or something else that could. The evidence base to be able to find a measure that could lead to a regulatory approval. We've got to meet with them to see whether they would accept, the data. But certainly, they've acknowledged how incredibly difficult it would be to conduct another trial when a therapy is already on the market signals to us their openness.
They've said as much in our pre-NDA meeting where they said, "We want to look at this further. Come back to us in the future." So we'll certainly look to do that later this year once we have visibility to the Parasol work. Fantastic.
So Rob, the company is guided to 2026 launch, in IGAN. Can you talk from your, from your clinical perspective? Can you talk about, patient numbers? That's still debated, even amongst clinicians. And also, as you think about where B-cell modulators will fit in that first-line, second-line combination treatment and your acknowledgment that nephrologists are a conservative bunch, since you are one of them, what is needed to get that sort of conservative bunch to take a biomarker and say, "Yeah, this is first-line"? I mean, Barrett knows, Barrett talks about, disease, functional cure. But what does it really take to get a conservative bunch to do that?
Yeah. I'm going to give you, maybe a little bit of a provocative thought.
Please.
Engaging response to that. I, I agree with Eric and Mitch. Patients who have hematuria or proteinuria or are found to have a slightly depressed GFR are getting referred to a nephrologist before they've had a biopsy, right? The general practicing community doesn't want to deal with those issues on their own. They want to hear from a nephrologist. It's at that point that they're likely to start an ACE inhibitor or an ARB or maybe in the future an endothelin receptor antagonist. And they make it started on SGLT2 inhibitor because they have chronic kidney disease. And we know that part of good CKD hygiene is to use those agents. Now they go and they get a biopsy. And now they have, have confirmed IgA nephropathy. Now they're going to get their first prescription. For IgA. They may already be on those drugs. They are already on those drugs.
So to say that they're first-line. Well, they're on board already. So they weren't prescribed because they have IgA nephropathy, at least the RAS inhibitors and the SGLT2s, right? So we're now in a situation where we say, "What's the first drug that will be prescribed when a diagnosis has been made that reveals that they're forming immune complexes and they're depositing in the kidney?" And I think the future will be they'll get a drug like atacicept that can turn off the faucet that immune complex generation holds off. That's the future. So yes, we have all these prescription databases that inform us on what patients are on. And IgAN patients are on ACE inhibitors and ARBs and SGLT2s. But they're not, they weren't prescribed them necessarily after they had their IgAN diagnosis. They had them prescribed before.
So it's now on top of what should the first intervention be to modify the disease that they've now been confirmed to have. I do think while it's maybe it's a, it's not as satisfying as what everybody wants to hear, I do think that there's white space right now for what first-line IgAN prescription is going to be. And I think it's going to be with a dual BAFF APRIL inhibitor, like atacicept.
Just quickly, patient numbers.
So we know in the U.S., and I agree with Eric. So we know in the U.S. that there's about 150,000-160,000 prevalent patients with IgA nephropathy. Numbers are similar and higher in Europe. We know that in Asia Pacific, they're high as well. And I think if we look at the opportunity to intervene, we're looking to treat patients who are forming immune complexes. And so it'd be very difficult to think about a situation where we know based on pathology that their glomeruli are clogged with immune complexes. And we're going to choose not to turn off the disease process. So in many ways, the question is, why wouldn't we be trying to address every one of those patients that has a biopsy that reveals the underlying mechanism of their kidney pathology?
All right. We have five minutes for lightning round. So I think, Mitch, we'd be remiss if we did not talk about your broader development scope for, for povetacicept, is that. So can, can we get your thoughts on, based on your learnings from your Phase I from IgAN, how are you thinking about developing it then in lupus nephritis, PMN, and even beyond that to autoimmune cytopenias, MG, lupus, and, and beyond?
Yeah. No, that's the goal for the company is really to take POVA in a very broad development plan. It's something that we're actively investing in. So we have two open-label studies right now. One is RUBY-3, which is our renal basket trial that has IgAN, PMN, and lupus nephritis. And we just added ANCA vasculitis to that as well. Then we have RUBY-4, which is our cytopenia basket trial, which has ITP, WAHA, and cold agglutinin disease. So, you know, we reported out a sentinel patient in PMN and ASN last year where we saw full immunologic remission. We'll continue to, you know, enroll more PMN patients in the RUBY-3 trial. And hopefully, we'll see more immunologic remissions in that very difficult-to-treat disease. In terms of the cytopenia basket trial, you know, ITP has been the predominant cohort that's enrolled in that.
We'll report data out from RUBY-4 probably in the middle of this year. But we're also getting WAHA and cold agglutinin disease patients into that as well. So the more broadly we can take POVA beyond just renal indications is very appealing to us. We're starting a Phase II placebo-controlled trial in lupus that'll launch by the end of this year. That trial is going to be called Denali. We have deep experience in lupus, both professionally through our clinical development team and obviously through our relationship with AbbVie and a CSL collab there. So, you know, and Benlysta has been approved in both lupus and lupus nephritis. So we think there's a real role for dual BAFF/APRIL inhibition in lupus and lupus nephritis.
But the goal really is to start to go after where the FcRNs have had success and having a broader Ig response than just IgG alone and being able to hit IgA and IgM and even IgE, right? So the concept to be able to do that and have a very broad development plan for POVA for us as a development team is what's the most exciting. Obviously, IgAN is the most near-term for us. And it's the most validated given the breadth of data in the space. But the ability to take POVA and other indications, we think it's going to be very interesting for the company to go forward.
So everyone wants to forgive me for asking a non-IgAN question. We have a captive audience and piggybacking is important to Travere. So, ongoing Phase III program, 2026 readout. Maybe you could just briefly discuss why you think it'll work and what the opportunity in HCU is.
Yeah. Thank, thank you for asking, because this really is an exciting program, not just for us, but for a community of patients, that with, classical HCU, that really have nothing other than a phenomenally strict diet of essentially maybe 10 grams of protein a day. This is a patient community that, you know, will oftentimes have a stroke by the time they reach 25, and are desperate to have something that would be disease-modifying. So pegtibatinase is a, a recombinant humanized, enzyme replacement therapy that it, that just entered into Phase III.
We're on track for top-line data readout from that trial in 2026, with a very innovative trial design that not only has surrogate endpoint of total homocysteine as the primary endpoint, but also for the first time, is very rigorous in the measure of additional protein into the patient's diet, which is the number one need that we hear from patients in this disease. So we're very excited about it. This is a multi-billion dollar sized market opportunity with nothing else on the horizon other than pegtibatinase. So we're very excited about the progress that we've made there.
Rob, just very quick, 96-week data is coming. What should we expect?
I think a very similar profile than we showed at 1.5 years. I think we'll show for two years. It's a quartet of Gd-IgA1 reduction, resolution in hematuria, reduction in urine protein excretion by about 50%, and stability in GFR consistent with the general population.
When will we get first biopsy data?
First biopsy data.
Oh, oh, for one disease? Yep. Followed by two days.
Yeah. So that's in the planning process now.
Okay. Great. With that, I think we are actually done.
Yeah. That was tremendous. Thank you very much.