Afternoon, everyone, and thank you for joining us for our next session. My name is Matt Keller. I'm a vice president here at Wainwright, in the research department. The next company we'll be talking to is Alpine Immune Sciences, and here to talk about Alpine we have Remy Durand, CBO of Alpine. Welcome, Remy. Hope you're doing well. Hi, Matt. Thanks very much. Thanks very much for having us, and thank you to everyone who's listening into the webcast here. Yeah, so for the sake of time, let's just jump right into it. You know, our team in H.C. Wainwright are obviously very familiar with the Alpine story, but I was wondering, to start, if you could give a very broad overview of Alpine and, possibly also introduce your lead asset, povetacicept. Yeah, absolutely. So yeah, it's a great way to start things. So Alpine is a clinical-stage immunotherapy company where we're focused on developing innovative treatments for autoimmune and inflammatory disease. The company was actually started in 2015, and the goal was to create novel, first, and best-in-class protein therapeutics that would work against multiple targets within the immune system. So our rationale is always first and foremost scientifically and clinically driven. All of our molecules have been developed internally using our directed evolution platform. Using that platform, we created our lead wholly-owned program known as povetacicept, or ALPN-303. This was discovered in-house, and at the last ASN meeting in the fall, we shared our first data in glomerulonephritis, including IgA nephropathy, which demonstrated that povetacicept is a potentially best-in-class, dual inhibitor of the BAFF and APRIL cytokines. BAFF and APRIL cytokines are critically important. They play key roles in the pathogenesis of multiple autoimmune diseases, including lupus and including IgA nephropathy. So what—what really fundamentally differentiates povetacicept, though, from other molecules in development is that using our directed evolution platform, we've engineered the molecule to inhibit both BAFF and APRIL with significantly higher potency than wild-type TACI-Fc, with a particular emphasis on improving APRIL binding. We've also shown just recently, preclinically, that there are unique properties of the molecule, including its, its better affinity, that potentially enhance its tissue distribution to target tissue organs. The story is actually fairly broad, though. We envision the development plan for povetacicept to be across multiple indications, similar in vein to what we've seen from FcRn inhibitors, where we have a—you know, a development plan that includes IgAN but also includes lupus, autoimmune cytopenias, other autoimmune kidney diseases, and importantly, we formulated this in a convenient once-a-month subcutaneous regimen. Again, that does enable, in our view, a very broad development plan, across multiple therapeutic areas. So maybe I'll pause there, and we can dive into anything you like. Yeah, absolutely. You know, you're—you're kind of reading my mind. Obviously, one of our big, a big points of our thesis is obviously the dual inhibition of the BAFF and APRIL pathways, but, kind of also going back to what you're talking about, the first indications that you're really going after were IgAN and kidney disease. Just briefly, again, could you just talk a little bit about why that was, and maybe talk about the market opportunity that you have, in that disease space? Sure. So we've always viewed povetacicept as having potential across, again, multiple therapeutic areas. IgA nephropathy, in particular, represented an attractive area. There had already been some activity in the space, demonstrating that inhibition of either BAFF or APRIL together or APRIL alone might have a beneficial effect on the disease itself or, importantly, a key biomarker of the disease. For those, you know, who may be not as familiar with the space, IgA nephropathy is driven fundamentally by an excess production of galactose-deficient IgA from the gut and the mucosa. That Gd-IgA1 then circulates, and the body develops autoantibodies against it as an autoantigen. That forms immune complexes, which localize to the kidney, which they then go on to cause inflammation and then eventually damage to the kidney and decrease kidney function. All of this, again, is driven fundamentally by an excess production of Gd-IgA1, which involves, critically, the upregulation of BAFF and APRIL. The formation of the immune complex also involves the cytokines BAFF and APRIL because those trigger, via plasma cells, the production of IgG antibodies, high-affinity IgG antibodies, against the antigen. So the role of BAFF and APRIL here has been also validated genetically. We know there's upregulation for the genes that can upregulate on this pathway. So there are several data points altogether that sort of form a constellation and support the development of BAFF and APRIL inhibitors for IgA nephropathy. And so that fundamentally is the rationale. In our view, again, we saw the potential to develop a therapeutic with best-in-class proteinuria reductions, eGFR stabilization, and importantly, again, a convenient once-a-month dosing regimen. Yeah, and that's a nice segue, actually, into, I think, povetacicept's current developmental state clinically. You know, we have, as you mentioned, a clinical readout that just occurred coming out of the RUBY-3 trial. We have some takeaways, particularly it's, it's a very impressive both safety and efficacy profile, but I was wondering if you could talk a little bit more about RUBY-3 and some of your takeaways from that trial as well. Yeah, I think what was very clear coming out of ASN, from the general community, from our investigators, also from investors as well, was that the proteinuria reductions we had demonstrated were, you know, clearly best-in-class and support the best-in-class potential for the molecule. And just to summarize everything, at six months, we observed a greater than 50% reduction in UPCR, and that's the proteinuria, which is the primary accelerated approval endpoint. In addition to that reduction in proteinuria, importantly, we saw a high remission rate. And remission is a, I'd say, a concept that's becoming more important as we go on in IgA nephropathy. There is no agreed-upon definition of remission in IgAN, but what we used was a fairly strict set of three criteria, which included a reduction of proteinuria by more than 50%, a reduction of proteinuria below 0.5 grams, and then also stabilization of eGFR. What we found was that, about 80%, or 4 out of 5 of the patients at 6 months, were able to achieve remission by these standards. Importantly, we also saw clear reductions in Gd-IgA1 and this biomarker, and also reductions across IgA, IgG, IgM, and then new data here was also in IgE, which opens up potentially a new angle for us to develop in IgA-mediated diseases. I'd say, you know, beyond this data, what's important to note in terms of trends for IgAN overall is that this market is actually, I think, fairly large, and it's probably much larger of an opportunity than many of us had appreciated early on. There are patients who have IgAN. There are many patients who are undiagnosed in terms of their IgAN, but there's an increase in awareness amongst the nephrology community that they should be screening for IgAN, I think, more frequently than they are now in the United States. In Asia, the apparent rate of diagnosis is higher, but that could be due to just increased screening. The other important trend in the IgAN space is an increasing understanding that these are young patients, and that having proteinuria, even, you know, around one or even below one, is dangerous for them and increases the risk substantially to go on to end-stage renal failure. Even, you know, patients between 0.5 grams and a gram, they have upwards of 50% risk of going on to end-stage renal disease. So there's a major push now amongst the community to be treating these patients earlier and treating them more aggressively. The other piece that's critically important here is that the BAFF/APRIL class overall has demonstrated that this is a disease-modifying potential. What I mean by that is we're seeing a reduction in Gd-IgA1, and then importantly, we're seeing a stabilization in eGFR, which is a long-term outcome that we want to be able to measure and achieve for these patients. All of that's a major paradigm shift for these patients who, until now, were really just, you know, best-case scenario, hoping to decrease the slope of their eGFR decline. Now here we have this potential class, a way to stabilize eGFR. Then again, with povetacicept, we're seeing the deepest proteinuria reductions, stable eGFR, and a best-in-class once-a-month regimen. Yeah, and again, it's the improvement in all those outcomes. As a summary, that we don't use the phrase lightly, but a best-in-class, I think, label is something that this is slowly beginning to actually mature into, right? That kind of goes into my next question is, you know, as good as this looks, and assuming it holds up in later-stage clinical trials, where do you see povetacicept kind of fitting into the treatment armamentarium? You kind of commented a little bit on it already, but where do you, where do you see it fall? As a monotherapy, as a combination, et cetera? What are your outcomes? Yeah, well, one of the attractive pieces of povetacicept is that it can be combined, of course, with other therapies. So I think taking a step back at the IgAN landscape overall, you know, what we see are, you know, roughly 150,000 or so patients in the U.S. with IgAN, and roughly half of those patients will go on ACEs and ARBs and SGLT2 inhibitors and still not adequately respond in terms of getting their proteinuria reduction below a target threshold. So for those patients, I think what we're hearing very clearly now from the nephrology community and KOLs is there is no reason, once BAFF/APRIL inhibitors are available, that those patients should not go directly onto a BAFF/APRIL inhibitor. So I do think overall the BAFF/APRIL class is going to take a majority of that opportunity for patients who are truly diagnosed with a biopsy confirmed to have IgAN. I think that's where the BAFF/APRIL inhibitors will really dominate and be a game-changing therapy for these patients with IgA nephropathy. That being said, it is combinable. You know, for instance, in our own study, patients have to be on max-tolerated ACEs and ARBs. They can also be on SGLT2 inhibitors as well. So I think that's something you'll start to see for sure as combination, but I think the dominant biologic therapy there is going to still be BAFF/APRIL inhibitors. Yeah, absolutely. And circling a little bit back to the RUBY-3 study, I think another thing that came out of that too that was of interest to us is dosing and timing of dosing. You touched on this a little bit as well. But I was wondering if you could talk a little bit about the significance of having a relatively low concentration of drug at a relatively spread-out, dosing regimen and why that's important possibly for the future as well. Right. No, that's a very good point. I think it's a point that's also often underappreciated is that it's ideal really for patients to have as little amount of drug as possible. And that's one of the big benefits for povetacicept is that just administering 80 milligrams once a month is able to achieve this remarkable proteinuria reduction that we saw. That's better for patients. It's better for cost of goods, of course. It's better for the, you know, potentially for safety as well, to have fewer injections, to have a lower amount of drug. And so these are all really critical points. As part of our platform and what we do early on in screening is that we look for molecules that are well-behaved, that are stable, and that are straightforward to manufacture, and that's, of course, what we have with povetacicept is a very well-behaved protein. It's fairly small. It's smaller than the wild-type proteins. We only use one of the cysteine-rich domains. Of course, it's quite potent. And as we saw, it's able to distribute, at least in mice, into target tissue organs better than the wild-type TACIs. So the other piece, of course, is just patient convenience. You know, we said before enrollment in our 240 mg arm is going quite well. We had already sort of announced that we were over-enrolled or that we had exceeded enrollment in 240 mg once a month versus 80. We continue to enroll patients there. And the demand that we're getting from investigators and from patients as well to be on the study is just so encouraging to get that feedback, even at this early stage of development, or I'd say especially in this early stage of development. It shows the interest. It shows the market opportunity as well. Anytime we've presented patients with this profile and the opportunity to go on a once-a-month therapy, there's no reason not to choose that, I think, versus, you know, a more frequent dosing regimen. Yeah, it's definitely, again, for us, it's a huge part of the thesis and why, why we're really standing behind povetacicept. But again, I want to drill down a little bit because, as you mentioned, there's also some, there are plans and there is ongoing, looking at a higher dose, that being the 240 mg, right? You've already shown impressive efficacy at a lower dose. I was wondering for our audience and the investor community, maybe give a little bit more of the rationale behind why going a higher dose might be important or, you know, what impact that might have on current study designs or future study designs. Exactly. So we do have two: RUBY-3 is designed as a multi-dose dose escalation study testing both 80 milligrams once a month and 240 milligrams once a month administered subcutaneously. We started with the 80, and now, as I said, we're dosing on the 240. And the reason for that is a few fold. One is we do plan in other indications potentially to explore a higher dose. So, you know, such as lupus, we probably plan on most likely 80 and 240 to be studied. We also want to make sure that we're actually not leaving efficacy, you know, on the table potentially with 240. What we've seen with 80 already is best-in-class. We actually are, you know, we want to see if there is even room for further improvement on 240? We've guided before that 80 milligram is a dose that we're planning to take forward to a pivotal IgAN study, but we want to see additional data, I'd say, right now still from the 240 milligram arm. We'll get a first look at the 240 data here upcoming at the World Congress of Nephrology. That's in Buenos Aires. Our presentation is on April 15th. It's a late breaker. And so that will be the time where we get two sets of data. One will be longer-term follow-up from our 80 milligram, once every month subcutaneous cohort. We'll have data there in patients out to nine months. And I'll just remind everyone, nine months is, of course, the approvable or is the accelerated approvable time point. The goal there is really to be able to maintain that greater than 50% reduction in proteinuria that we saw at ASN to show that that greater than 50% proteinuria reduction maintains at nine months. That's a big one for the company. The second key piece of data that people are interested in is, of course, the 240 mg arm. The data will be still fairly early in terms of the duration of follow-up, but it'll give a first look again at what we're seeing in terms of both UPCR, eGFR, safety importantly, and of course, other biomarkers as well. Yeah, and also speaking of timelines, you have a phase 3, as you also just touched on as well, set to begin around the second half of 2024, in IgAN as well. I was wondering if you maybe comment on the state of that trial, any rate-limiting steps getting that started, and maybe some details about that trial, what that looks like. Yeah, so right now our plan is, of course, to start 2 studies in the second half of the year. So we're very laser-focused at Alpine on execution. The pivotal IgAN phase 3 study will—we'll plan to start in the second half of the year. And again, you know, we can't disclose any details right now about the design of the trial. We feel like, you know, we're still on track to start that in the second half of the year. I can say it'll likely look very similar to other studies that are ongoing in the phase 3 IgAN space. And there's, you know, right now it's really just kind of operationalizing that, and getting that started in the—in the second half. Of course, we haven't given the—the definitive dose regimen. The plan is still 80 milligrams, but we do want to see longer-term follow-up from the 240 arm as well to determine which dose or doses we might go forward with. The second study then on execution, of course, is a phase 2 lupus study. As I said just earlier, now we are planning likely to take 80 milligrams and 240 milligrams once a month into that lupus study. So likely looking at a three-arm study. Again, that's slated to start again also in the second half of the year, likely after the IgAN study. Yep. Yeah, perfect. Yeah, that's, we're very excited to see that data, and we'll be looking forward to updates, later this year. Switching gears with some of the time we have left, we've always looked at Alpine, not only your internal programs, but your external ones too, the ones that you've partnered as well. Beyond, povetacicept, you also have another asset that you've partnered, acazicolcept. I was wondering if you could maybe give us an update on that program and how that's going as well. Yeah, so, we announced last year that this program, which is partnered with AbbVie, maybe just stepping back, this is a program we developed in house. It's an inhibitor of two T-cell receptors, ICOS and CD28. And we announced in 2020 an option license agreement with AbbVie to study ALPN-101 in lupus. At the end of last year, we actually amended the agreement, at our sort of insistence, to modify the terms such that we could end enrollment earlier, and also be able to sort of have a look at the data earlier. We were both interested to see an early look at the data. And importantly, what that does is that it frees up resources for Alpine to focus on actually on povetacicept more significantly. We've received $105 million in upfront and near-term milestones from it. We've built up a healthy infrastructure for Alpine around lupus and knowledge around lupus. The goal now is to have AbbVie enable a decision there and then focus our bandwidth, our resources on povetacicept. It's been a fantastic partnership. I think one of the challenges we've noticed with acazicolcept, though, is just that it's an IV every two-week formulation, which is why we did prioritize early on a once-a-month subcutaneous formulation for povetacicept. I would say, you know, really for us, the key milestones coming up, of course, are this first look for povetacicept at the WCN timeline. We also have—it's public now. We were accepted for an oral presentation at the European Renal Association meeting. That'll be around Memorial Day, in Stockholm. Those are the two main first half of the year catalysts. And then in the second half of the year, the operational catalysts are starting, these additional studies for povetacicept, or sorry, these studies in IgAN and lupus. Looking beyond 2024, you know, we're very interested in expanding the development pipeline for Povi in multiple indications. So last year in the fall, around the same time at ASN, we shared the first data in a model of myasthenia gravis, where we actually looked at least as good, if not better, even than anti-CD20 and anti-FcRn therapy. So that was a major, I think, step forward for the company. We'll have additional translational data coming out in another, autoimmune neuro indication this year as well, and then, of course, thinking about additional indications within renal and within the RUBY-4 cytopenia basket. I'll just remind everyone, at ASN, we also saw a very compelling case study in a single patient with primary membranous nephropathy. In this patient case study, we observed full immunological remission, which is a reduction of the autoantibody there, anti-PLA2R1 IgG. And so we essentially eliminated that patient's anti-PLA2R1 IgG levels. And now monitoring, we would, you know, typically for the course of the disease, you observe a proteinuria reduction following immunological remission. So PMN for us, primary membranous nephropathy, is a very interesting, compelling indication. Within the autoimmune blood disorder or autoimmune cytopenia baskets, warm autoimmune hemolytic anemia stands out to us. There are no approved therapies in this space. The pull that we get from physicians in our research is very clearly indicative of a demand for new therapies there. So that's something we'll continue to study. Ideally, we'll be able to share some data from our RUBY-4 basket study in the first half of the year. It'll likely be around ITP, potentially some anemia data there as well. But that's another, you know, another potential catalyst for us as we go forward. So along those lines, I mean, as I think Remy kind of, put out there, and as if you look at the website, you look at the pipeline, there's a lot going on in the Alpine pipeline, you know, and going back to that - the BD topic, is there any considerations for partnering or - or outlicensing some of these in order to progress them a little bit faster? No, I mean, we think there's still a lot of value that we certainly will generate on our own here. I think there's—these molecules have tremendous potential, or povetacicept has tremendous potential. And we plan to take those forward and take the molecule through these important additional catalysts, in the next couple of years. In addition to that, I'd say we're actually more focused internally on our discovery pipeline as well. We've always invested, you know, substantially into our discovery pipeline. That team is now really focused on immunology programs and immunology targets. We're working to be able to get those into the clinic and prioritize those as soon as possible, hopefully be able to share something towards the end of this year on what that discovery pipeline looks like. And, you know, we feel it's pretty exciting, and we hope that the community will as well. And again, sorry, go ahead. No, that's. Along those lines too, one of the things that we've always been impressed by is you have Alpine has always maintained a very strong balance sheet as well. And I was wondering in the couple of minutes or a couple of seconds we have left, if you could maybe give a little snapshot of what that looks like and what your capital deployment might look like over, let's say, the next 12 or 18 months or so. Sure, yeah. On the back of the data at ASN, it was very well received. We were able to raise $150 million from top-tier investors. That puts our current balance sheet as of 12/31/2023 at $368 million. So we're very well capitalized. We have a lot of strong investor demand for the company. I'd say we're squarely focused on operations right now. That balance sheet takes us into 2026. That's what we're focused on, and we think, you know, we'll create additional value, certainly over the next year or so with hopefully these readouts coming up. Fantastic. You know, in the last couple of seconds and minutes that we have, one last question, really give you the opportunity if there's anything that you'd like to share with our audience that we weren't able to mention in the last 25 minutes or so, catalysts, milestones, or anything ongoing in the pipeline that you'd like to put out there now. Yeah, I just want to reemphasize, of course, you know, again, povetacicept, this is a molecule that we developed internally in-house. It is wholly owned, and we have substantial expertise on this pathway. The opportunity, of course, in IgAN is very attractive. You know, there's no disease-modifying therapies approved right now. And our goal is to advance povetacicept in IgAN with the best-in-class profile in terms of potency, you know, safety, and also dosing frequency as well. Again, just to emphasize, the opportunity is much larger than IgAN by itself. We envision, you know, developing povetacicept. We plan to develop povetacicept across multiple indications. Lupus will be that first indication outside of IgAN, but then the opportunity itself that we've showed in translational models includes autoimmune neurological disorders, autoimmune skin disorders, and then autoimmune cytopenias as well, in addition to large rheumatology indications like lupus and Sjögren's. So that's really what I want to emphasize. Again, developed internally, owned outright, and massive opportunity across multiple autoimmune indications. Behind this program, of course, we have our discovery platform. We continue to invest in there. Given our track record of advancing molecules to the clinic, we're also hopeful to drive additional innovation outside of our, you know, using our discovery platform. So just really emphasize, we have an active pipeline, povetacicept moving forward in multiple indications. But we're also, you know, very excited about what's in the pipeline. Yeah, and so are we obviously always behind Alpine. We're very excited to see again what happens, in the next couple of months or so. With that, I think we're about out of time. I want to thank Remy and Alpine again for joining us for this fireside chat. Hopefully we'll talk soon. Thanks, Matt. Thank you, everyone listening in. Yep, appreciate you, Matt.