Good morning. My name is Liisa Bayko. I'm a biotech analyst at Evercore ISI, and welcome to day three of our healthcare conference. Very pleased to have Alpine with us here for our fireside chat, Remy and Mitch, kind of leadership of the company, CEO and Chief Business Officer. And I've been following the IgAN space pretty closely, and this is one of the companies I think has got some, you know, obviously very interesting data, and in an area that's really, really important, which is modulation of B- cells. But I'm gonna turn over to Mitch to give us an overview. Yeah. Thanks, Liisa, and thanks for having us, and I agree, you do a great job covering the IgAN space, so thanks for doing that. So Alpine's a company that we founded in 2015, and first and foremost, we're scientifically driven. So our goal is to create new molecules that can really improve patient care. The goal of the company was to create multi-specific proteins that can modulate the tight junction of the immune synapse. So we've created a number of molecules out of our platform, which we call a variant Ig platform, that allows us to create multi-specific proteins. We've brought two molecules into the clinic off of that platform, or three, I should say, molecules into the clinic, but the focus for the company today is our lead molecule called povetacicept, which is a dual inhibitor of two B-cell cytokines, both APRIL and BAFF, that has just reported out its initial phase I/II data in IgA nephropathy at ASN a couple weeks ago. Now we're pushing that program forward into a pivotal study in IgAN next year, as well as into a phase II study in lupus next year. We have a very broad development plan for the program. We don't look at ourselves as an IgA nephropathy company. We look at ourselves as a broad autoimmune and immunology company. Because of that, we raised $150 million a couple weeks ago, which gives us just over $370 million of cash, which allows us to really prosecute a broad development plan for povetacicept across a number of indications beyond IgA nephropathy. Great. So, you presented some, your first kind of, like, look at data at the ASN meeting last two weeks ago, three weeks ago? Yeah, November 2nd. Yeah. Yeah. It's all a blur now. Maybe you could just give us an overview of kind of what were some of the key findings. I mean, we were very pleased with the way that data ended up reading out. So first off, the trial enrolled very well, and it continues to enroll very well. So there's tremendous amount of investigator interest in putting patients on B-cell modulators that will impact the main cause of their disease. The data that we presented at ASN showed, first and foremost, a UPCR reduction of just over 53%, which is potentially best in class. But we started to bring up this concept of remission rates, and I think you're going to continue to see this concept of remission rates come in more and more to the forefront. So we showed that 80% of patients met three remission criteria at six months, and that was, they had to have a greater than 50% reduction in their UPCR from baseline, and they had to have a UPCR of less than 0.5 grams per gram, and they had to have their eGFRs being stable. In fact, ours went up just a bit, but we called it as being stable. And when you apply all three of those criteria, 80% of patients met that remission criteria. That's a different remission criteria than kind of standard, correct? It's more stringent- Okay. -than UPCR. That's exactly right. So that remission criteria... And I think how we're going to define remission as a field is still in flux a bit, but that was the most stringent set of criteria- Okay -that we can use. But just to put in perspective for you, like in the New England Journal publication that came out for Sibi, when they used just the 0.5 grams per gram, I think, what was it, like 29%-ish? Yeah. 30, around 30%. Yeah. Just on that- Just on that one criterion. ... reduction alone. Your stock had a big move after the data, and one thing that kind of always I want to just keep in mind is, like, you know, it's a very small sample size still. Yeah. How comfortable are you with that? Maybe you can remind people. Well, I think Sorry, how many patients was it again? There were five patients that we reported out at six months. Okay. There's over 20 patients that have enrolled in the trial. You know, we gave some guidance that, you know, we were enrolling in the 240-milligram cohort as well. I can tell you now, the 240-milligram cohort's actually exceeded the number of patients that we've had in the 80s. So the enrollment's continuing to go very strong for the trial. I think the reason that there is deep investor interest in that data is probably multifactorial, and you know this better than I do. One of it is the targets themselves are extremely well-validated. So whether it's BAFF with Benlysta, or APRIL with other programs like Chinook and Otsuka's molecule, there's a lot of comfort around the targets themselves. Two, there's comfort in the space, and investors are very good at creating comps, and I think they're comfortable with UPCR as being a good proxy for, you know, overall treatment effect for these types of drugs. And so our UPCR reductions clearly were impressive at 53.5% when you compare it to most other molecules in the field at around 30%. So I think that's what drove investor interest in the story. We've seen, though, like, other companies, when they kind of present, you know, you know, bigger cohorts of data, actually, the data changes quite a bit. So I guess- Yeah, no, it's something that we're obviously- We're comfortable with ... We're... We're obviously aware of that. No, we're aware of that, and, the way we look at that is a little bit different. You know, if you look at, without getting into specifics, a lot of that has been, for example, when companies have transitioned from an IV formulation- That's true ... to subQ. That was one of the other factors. Yes. And so I think one of the key elements for povetacicept's presentation at ASN was this was a once-a-month subcutaneous formulation. Mm-hmm. The data was strong enough, and when we talked to the KOLs there, there was really strong sentiment from most of the investigators that the data were so impressive that they were pushing us to go directly to a pivotal, which is what we're planning on doing with the 80-milligram dose. Obviously, we'll continue to track 240, and if it looks dramatically better, we can pivot the pivotal study to a 240 dose, but the 80-milligram dose was strong enough, and it is already our subQ formulation. What was the baseline proteinuria in your patient cohort? It was very consistent. The other thing was, like, 1.3, 1- One, yeah. One point- On average? Yeah. Mm-hmm. And I think, so that was another - thank you for bringing that up. That was another point, which is - when you look at the baseline demographics of the data that we presented at ASN, it was very similar to other global studies that you would see with IgA nephropathy, in contrast to some of the other data sets that were presented there, where it was mostly a heavily predominant Asian population. Yeah. It's interesting, like, I, I feel like in the field, so proteinuria is a leading indicator of eGFR, but it doesn't, like, really correlate numerically that well, it doesn't seem, right? It's just more of a directional thing. Is that, do you, do you agree with that? Yeah, I think it's been clearly directional. I think it also one of the key messages from John Barratt and some of the other KOLs, too, is that not all proteinuria reductions are the same, and we heard that over and over again. And that I think what he means by that, in particular, is that targeting the BAFF-APRIL space, the proteinuria reductions you get there are disease-modifying, and they're, in a way, more meaningful than proteinuria reductions with other non-disease or supportive care mechanisms. And I think that's supported with the Gd-IgA1 reduction. So to see the proteinuria and the Gd-IgA1 reduction together, I think that's a more meaningful impact or a more meaningful readout than just either alone, for instance. Okay. It's not just the hemodynamic features of a molecule that's reducing proteinuria, it's actually you're changing the root cause of the disease. Right. Right. Right. Right. I think the other piece where there was so much interest coming out of ASN was also the molecule was well-tolerated, and it's not something that gets discussed a lot, but having that safety data, this has helped as well. And also, this was in a very low amount of drug. This was 80 milligrams dosed once a month, and we're seeing such dramatic activity at this low dose. I think that also was appealing to investors as well. I think that's a good point, Remy, which is when you look at the amount of protein that we're giving to the patients on a monthly basis, it's 80 milligrams of protein a month. And if you compare it to others that are in development now, they're anywhere between, you know, 400 milligrams to over 1 gram of protein being administered a month, you know, either weekly or biweekly. Yeah. Right. And then I think the last point coming out of ASN is we did have a case study in another indication, in primary membranous as well, which showed a dramatic, reduction in, key autoantibody in that disease. So now, you know, for us to be able to build a story, show activity in IgAN, but also build beyond IgAN, I think that's, that resonates very well, and that was a lot of the questions we got from investors, was IgAN, and then, "What's next? And how do you build upon this data set? Mm-hmm. Okay. There's been a lot of controversy in terms of, like, what does, you know, BAFF, BLyS bring to the table- Yeah ... you know, above and beyond what you can get with APRIL. And I think as you go into other indications, I think BLyS becomes a more important factor. Yeah. But where do you land on its role in IgAN? Because we've seen good data from just APRIL alone... Yeah ... molecules, too, you know, and we've you know, kind of hinted at a couple of them. There is one from Sanofi known now to Novartis. Yeah. Obviously, sibeprenlimab. So where do you kind of land on that whole dynamic? Well, first, we designed povetacicept not to be an IgAN-specific molecule. Right. So when you go back to the design of povey, our team had worked on atacicept when they were at ZymoGenetics, which was another Seattle company. Yeah. When we started the company in 2015, and our protein engineers started using our platform, they knew some of the liabilities associated with atacicept, and they engineered povey to have much stronger APRIL binding than wild type- Okay ... and then atacicept itself. So when you think about BLyS in terms of IgAN, you know, if you look at kind of a BAFF transgenic model in mice, where BAFF is overexpressed, those animals will, you know, spontaneously get IgA nephropathy just on BAFF alone. So when we think about it, we think about it two ways. You need APRIL. You need potent APRIL to get very rapid reductions in Gd-IgA1, but you need BAFF for long-term remissions. And so we'll have to see this play out over time. But if you look at our remission data, at six months, it's the highest that we've seen in the field. And if you compare that to the pure anti-APRILs, where we mentioned they're seeing about a 29% remission rate at a year, right? I think you need BAFF to get those remissions that we're starting to talk about. It's really interesting you're saying that. So, like, you know, what features can you kind of drive towards in your data? And maybe it's longer-term data, as you mentioned, to really kind of try to distinguish this, so something beyond just proteinuria, right? Because, like, a lot of these molecules get to a fairly similar level. And even with sibeprenlimab, we saw, like, you know, kind of eGFR was relatively stable. Mm-hmm. If all the molecules can do that, then maybe kind of having BLyS and some sort of longer-term benefit on remission would be a differentiator. Anything in reaction to that or other thoughts on how to differentiate with that? Yeah, Remy does a lot of our CI work and our, kind of, commercial assessment work, so he's gonna wanna chime in, I'm sure. But I'll give you my two cents on it, which is, I think as a patient, you know, these are younger patients, they wanna see rapid reductions in the proteinuria. Their goal is to, you know, preserve as much renal function as we can and to keep them off dialysis. And, you know, like, most of these patients will progress to dialysis within a 10-year period. So these are young patients, and obviously, dialysis has a lot of morbidities associated with it. So the more we can keep them off dialysis, the better. I think with a program like povey, because we bind the APRIL and BAFF as potent as any others in the class, we can get rapid reductions, which is very reassuring to the patients and physicians. But then you can start to introduce this remission rate, which includes eGFR, which is an important component of that. Yeah, I agree. I think, you know, to a specific data point, it'll come down to longer-term remission and even longer-term follow-ups in terms of progression to end-stage renal disease, and that's ultimately, you know, what will differentiate, the program, I think, versus inhibitors of either alone. I also think, you know, we do plan on building a fairly large development plan, and having data across multiple indications, I do think builds the evidence and confidence around it, you know, for each individual indication as well. I think biologically, it's clear that, you know, BAFF plays a role in B-cell development. It's overexpressed in IgAN patients as well, and it's known that these two cytokines can compensate for each other. So I think rationally, dual inhibition should be better, and again, as we've seen, we have among the highest remission rate, and we'll follow that over time. And another thing I would say, you know, keep in mind that, and this kind of gets lost now, but, you know, it's a once-a-month dosing regimen given subcutaneously. At 80 milligrams, that's roughly a 0.5 ml of injectate, so it's a very low volume of injectate. Yeah. It's 80 milligrams of protein once a month, and the data that investors have seen is, you know, at that dose level. So I think that's something that in some ways, you talked about the small data set, but that's comforting, right? How do you see the market evolving? You know, there's a lot for... You know, it's funny 'cause now as you talk to physicians, we're all already or KOLs, we're already talking to them about, "Okay, well, you'll put your patient on this, and you'll kind of wean them off of this and put them on that." They're like, "Well, we don't even have anything today. Yeah. Right? But there, there is a huge pipeline coming. Right. How do you see the market evolving? Like, obviously, we have filspari now, atrasentan will be approved. Yeah. So we have kind of that class of drugs. And then you have this whole wave of B-cell modulators coming. Sibeprenlimab, you know, might be one of the first to reach the market, and it's gonna be a once-monthly as well, so you're coming a little bit later. You know, how much of a disadvantage is that? I think the sibeprenlimab data was, in our mind, it was impressive data. Mm-hmm. Mm-hmm ... on one level. On the other hand, it's an IV, weight-based- Right - dosing regimen. So we need to see, like, as I mentioned at the beginning, we've seen deterioration of data sets- Yes ... when they go from IV to subq formulations, and particularly here, when you're going from a weight-based dosing to now have a much more kind of global dosing schedule. So, when you look at, we see B-cell modulation, whether that's the wild-type TACI's, the anti-APRILs, or a program like povey, where it's a dual inhibitor of both APRIL and BAFF- Yeah ... as playing kind of a core central role as foundational therapy for patients with IgAN, and we see it taking up a majority of the marketplace there. Of course, you're gonna see RASIs and SGLT2s, you know, playing an important role, but it'll be the B-cell modulators. And the physicians are telling us this, that's the foundation of care for patients with IgAN nephropathy, and we see complement coming in in the later stages. But B-cell modulation, there's no doubt about it, will be foundational for these patients. Yeah, absolutely. I think different pathways are involved here, but it's clear that B-cell modulation is core to, to modifying the disease itself. And so it's... I think what we learned from our experience in our own market research is that the IgAN market is larger, I think, than a lot of people, including ourselves, thought in the beginning. So in and of itself, it's a large market, and I think the majority of that will be split between the B-cell modulators. Of course, SGLT2 inhibitors are coming up. There'll be some place for the endothelin blockers as well, and again, the complement inhibitors we see as potentially last line. Any kind of takeaways from the launch of filspari so far? Yeah, I think it's, it's hard to read too much into it, just given the noise around the data and the space. You know, we'll see, I think, at the end of the year, how their next interactions go, and into the next year. But I think there's still work to be done. But again, what we hear consistently is a desire for true disease modification as opposed to modification of, of the plumbing- Yeah, we did, Jigming and I actually did a call with the IgA Nephropathy Foundation. We just got, like, you could just see, the people who are on the board, actually, a lot of them are either parents or patients themselves. Yeah. Their faces just lit up when they kind of talked about B- cell modulation, which is, like, very, you know, very obviously- Yeah ... very excited about it. No, that's encouraging, and it's consistent. We speak with them as well, and the feedback that we hear from the foundation and from physicians and patients as well. Okay. Tell us a little bit about kind of where else you're going with povetacicept type stuff? I think for us, that's what's exciting as a company, which is how do we build out povey much more broadly? We're fortunate that we're sitting on just north of $370 million of cash on our balance sheet, which allows us to legitimately think about a very broad development plan for povey. Let me highlight, povey is the only dual APRIL-BAFF inhibitor that's unencumbered, meaning that we have no downstream milestones, no downstream royalties that we owe to any third parties, and it has composition of matter intellectual property out to 2041. Wow ... potentially beyond with extensions, right? So it's a pretty unique profile for a molecule in this space. So because of that, we're gonna prosecute it very broadly. So beyond IgAN, we've announced that we're gonna start a phase II study in lupus next year, and we have confidence there based on some of the other data- Lupus broadly or lupus nephritis, or what are you thinking? Lupus broadly. Generalized lupus. Like SLE? Yes. Okay. Yeah. And, and Remy can talk about that in a bit, but there's obviously validation there between Benlysta and then telitacicept that they've had on their Chinese-only population. So we think that that's obviously a huge market, where you have, like, 500,000 patients, roughly. Mm. Yeah, so it's a huge patient population for us to go after in terms of lupus indication, and there's validation for the two targets in the space. We have interest in myasthenia gravis. I don't know if you saw, we presented some preclinical data this year comparing us to FcRn as well as anti-CD20s, and we looked superior to both of those molecules. Then, obviously, we have RUBY-4, which is our cytopenia basket study, which we'll get more information coming out in the first half of next year, looking at wAIHA and ITP. So we really do have a very broad development plan, and Remy mentioned PMN earlier. We have this one case study in PMN now, where we had immunologic remission, which is at 99% reductions in anti-PLA2R, which is a pathognomonic antibody in that disease, and if we can get four or five more patients that look like that, we think we have a clear path towards pursuing PMN as well. So we are really- we do really have a very broad aspirations for taking povey into, like, a very FcRn-like development plan because of the way the molecule looks right now. The goal is to have a steady cadence of readouts every, you know, every quarter, every half a year, and be able to show activity in multiple indications, and again, build a bigger case to go after these indications. The indications that we select are all based on the role that autoantibodies play in these diseases, and that's really the target for povey, and that's what allows us to go into these different indications, rheumatology, the renal diseases, connective tissue diseases, cytopenias, and then, as Mitch mentioned, even neuro and potentially dermatology. There's many areas we could take it, and the goal is to build a platform that can address different needs. Right. So, just kind of bigger picture, you know, what, what are your aspirations? Are these things you wanna, like, you know, build a global pharma company, you know, kind of launch this yourself? Do you wanna, like, I don't know, f- just partner it off, or- No, it's a po- Sell the company? No. What's the plan? Look, I think our goal is to help patients at the end of the day. That is our number one aspiration, and so as you mentioned, you talked to the IgAN Foundation. When you speak to them, you can't walk away without being motivated. So our goal is to create molecules that are gonna benefit patients that are suffering from life-threatening diseases, and that's what motivates us. That's why we want to take povey into so many different indications, and if we can do that successfully, I think we'll have a lot of options on how we pursue the company going forward. Great. Well, thank you for your time today, guys. Thank you. Thanks, appreciate it.