All right, let's get started, everyone. Thanks for joining us on day three of the Morgan Stanley Global Healthcare Conference. I'm Michael Ulz, the biotech analyst here. It's my pleasure to introduce the team from Alpine Immune Sciences, including Mitchell Gold, CEO, as well as Remy Durand, Chief Business Officer. Just a quick reminder, format for today is a fireside chat. But before we get started, I just need to read a quick disclosure. "For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative." And with that, Mitchell and Remy, thanks for joining us today, and maybe, Mitchell, I can just turn it over to you to make some brief introductory comments for- Yeah. Thanks, Michael. It's a pleasure to be here. Just a brief overview on Alpine, if you're not familiar with the company. The company was started in 2015. It's a Seattle-based company, and the goal was to create multi-specific proteins that can modulate the immune synapse. The platform has been very productive. We've created a number of molecules out of the platform, both in immunology and in oncology, although now we've shifted to being exclusively focused in immunology and inflammation. The benefits of the platform is it allows us to create fusion proteins that have very strong interactions against known targets. That could be on the T cell, like we have with acazicolcept, which is partnered with AbbVie, against two T cell ligands, both ICOS and CD28. But really, the focus for the company now is a molecule called povetacicept, and povetacicept is a fusion protein that's a dual inhibitor of two B cell cytokines, both APRIL and BAFF. In fact, you know, a lot of the data that we've generated with povetacicept, it's the most potent inhibitor of both those pathways. So on the BAFF axis, it's as potent, if not more potent, than Benlysta on BAFF. And in terms of APRIL, it has antibody-like affinities in terms of being able to block the APRIL axis. So this is a really important time for the company. I'm sure, Mike, you're going to get into it. But, you know, you know, last year, we completed our single ascending dose study in healthy volunteers. Later on this year at ASN, we're going to have our first clinical data come out, where we look at povetacicept in a number of glomerulonephritis indications, the primary phenotype being IgAN patients, but also some PMN and LN patients. I think it'll really kind of position 303 as being a molecule that's going to be incredibly important for patients going forward. Yep. Great. Thanks for that introduction, and maybe we can focus on povetacicept. Povetacicept. povetacicept, got it. Yeah. Maybe just, you know, you talked about some of the advantages of the dual BAFF inhibitor, but maybe talk about some preclinical data you have that, you know, maybe speaks to the potency or other properties of the molecule. Yeah. When we created the molecule, or when we were designing the molecule, the goal was explicitly to create a molecule with very high potency against BAFF and APRIL. But in particular, in our engineering, it was to focus on, on the APRIL potency, and to really bring that potency up relative to the wild type. And there are several assays that we've used to characterize the potency, and compare it to some of the different molecules, whether it's a wild type or a dedicated antibody against both. But primarily, you know, what, what we look at is the ability to bind and, and block signaling on APRIL and BAFF. And what we find is in a functional cell-based assay, where we're testing in particular BAFF and APRIL signaling through a cell, we find that povetacicept, it is the most potent blocker against either APRIL signaling alone, BAFF signaling alone, or the combination of having both APRIL and BAFF together. We've compared povetacicept against, as Mitchell alluded to, dedicated antibodies against BAFF, in particular Benlysta, dedicated antibodies against APRIL, and so sibeprenlimab or Chinook's protein, as well as wild-type TACI's. And again, what we find is povetacicept to be as potent, if not more potent, than the dedicated antibodies against either BAFF or APRIL, and then more potent than the wild-type TACI. The wild-type TACIs themselves, and our team at Alpine was involved in the early generation of atacicept when they were ZymoGenetics. The wild-type TACIs themselves are, you know, primarily BAFF inhibitors. They do have some APRIL activity, but not nearly as strong as the anti-APRIL antibodies or povetacicept. So I think what that allows us to do is, one, we can go after diseases- Yep ... like IgAN that are at the front of everyone's mind. Mm-hmm. Really, the goal for us is to take povetacicept into a very broad, almost like FcRn development- Yep ... right? So sure, yeah, IgAN will be the indication everyone's focused on initially, but as more data comes out in other indications, whether that's some of the other glomerulonephritis indications like PMN or data that we get in ITP, or, you know, we just presented some preclinical data this week in myasthenia gravis. Yep. The goal is to take povetacicept in a very broad- Yep ... development plan for the company going forward, because, as Remy said, we block both those axes so potently- Yep ... where the wild-type TACIs may be more limited in that regard. Yep. Makes sense. And maybe you can just touch on... You're obviously targeting B cells, but there's some other approved agents out there, like a Rituxan, that also sort of targets the B cells, and kind of what's the differentiation or advantage to the dual? Well, there's a number of differentiations. Rituxan, for us and the FcRns- Yep ... really kind of provide a roadmap for us for what indications we want to go after. And so we can look at where those agents are effective, and we know we can improve on it. Why can we improve on it? Because we're not a B-cell depleting drug. We know we affect how antibodies are made, are made by B cells, but we don't deplete B cells. We're given once a month subQ, as opposed to- Mm-hmm ... via IV. So it's a much easier way for us to kind of go after these spaces and much more convenient for the patients. ... Yeah, I'd say in addition to that, we work across a broader spectrum as well. CD20 is a fairly limited population of B cells. It misses several important B-cell populations that go on to propagate disease through production of pathogenic autoantibodies. By blocking both BAFF and APRIL together, we hit again a broader spectrum. And then, you know, even relative to the FcRns, we work much further upstream from FcRns. FcRns work towards the end of that production of IgG. The goal would be to work earlier on and be a truly disease-modifying agent. But as Mitchell alluded to, again, they do provide a roadmap, and our goal is to build on that, improve on that, and work more potently across more indications. Yep, makes sense. Maybe we can shift to the RUBY-1, you know, healthy volunteer data and maybe talk about what you saw on the safety side, anything notable there, and then also maybe the impacts you've seen across different antibodies. Yeah, the RUBY-1 healthy volunteer trial, which we completed last year, was our first in-human clinical trial for povetacicept, and we dosed all the way up to 960 milligrams, single dose. We saw no serious adverse events, even at that dose level. Mm. From the RUBY-1 study. Most importantly, we saw a very potent inhibition of immunoglobulin phenotypes. So if you compare us against the wild-type TACI, we are much more potent in inhibiting IgA, IgG, and IgM than the wild-type TACI. And we were in line with the APRILs, to Remy's point earlier, that, you know, we're the only drug that really covers both those axes, you know, so efficiently. You know, we also saw that we could get into a Q monthly regimen from the healthy volunteer trial. So we learned that at 80 mg, we covered the target for about three weeks off a single dose, and at 240 mg, we covered it for the full four weeks, which allows us to study both those doses going forward. At ASN this year, we'll be able to share for the first time what the 80 milligram monthly dose looks like in a multiple dose setting. Mm-hmm. So we'll see how we're covering the target there. That'll be our lowest dose, so about 80 milligrams a month. And just to give you a comparison for that, if you think about where Vera is, they're giving 150 milligrams of drug a week. So that's 600 milligrams a month, compared to povetacicept, which is 80 milligrams a month. Yep. Really gives you a sense of how potent the molecule is. Yep. So you're talking about the RUBY-2 study there. RUBY-3. RUBY-3. Yeah. Sorry, I'm mixing them up. Yeah. Thank you. Yeah, RUBY-3 is our glomerulonephritis basket study. Okay. That's ongoing. RUBY-2 is a trial that's in design. It's a lupus trial. Yep. Yep. Okay. Maybe just talk a little bit more, since we're on the topic, just the development strategy, the different buckets, you know, you're currently going after, where you are, and why you sort of chose to go after those baskets. Yeah. Again, it's a good roadmap for us because we can kind of look at where the FcRns and Rituxan has been, but really, we can look at any disease that's autoantibody mediated. So obviously, a number of the renal indications have autoantibody diseases. So for IgAN, this is obviously galactose-deficient IgA1, the complex that come out of that. For PMN, it's PLA2R. And so particularly for PMN, you know, that antibody, PLA2R, is almost pathognomonic for the disease. And in fact, when you drop PLA2R levels down, it correlates very closely with improvements in clinical outcomes. So that... You know, if we can, in the PMN patient population, show that we're dropping that antibody and we see appropriate improvements in UPCR and proteinuria reductions- Mm-hmm. That'll be a huge win for us in that patient population. There's really no approved drugs there. That'd be great for us going forward. On the heme side, it's the same thing. They're all- Mm-hmm autoantibody-mediated diseases that we can go after with a program like povetacicept that covers, as Remy mentioned, B cells, both early B cell maturation and late, you know, B cells, both plasma cells. Yep. And you mentioned sharing, I guess, the IgAN data at ASN coming up. Can you talk about the patient numbers? I think you suggested the dose would only be at the lowest dose. Is that correct or? Yes. So this would be our first look. It's at our lowest dose level. Yep. Just to give you a reminder of the trial design, it was five-seven patients per arm in IgAN. It was five-seven at 80- Mm-hmm and then five-seven at 240. You know, we have said that, enrollment was robust in, RUBY-3, particularly in the IgAN cohort. and so we'll probably over enroll, but we're not really gonna give any kind of insights into how many patients we're gonna get there. But we think it'll be a meaningful update that'll be, easy for investors to understand. Yep. Can you maybe talk about efficacy endpoints and how we should think about the bar? Yeah, for sure. So I think... Look, the bar in this space, this is why IgAN, I think, is such an interesting space from an investment perspective, because the bar has pretty much been set. Yep. So I think, you know, you know, Vera's kind of set the bar at 30% at three months. In that range, I think what's more important is not what you look like at three months, but what do you look like at six and nine months, and do you see appropriate preservation in eGFR? So for us, at our lowest dose level, if we can, at our lowest dose level, look similar to what, you know, Vera and Chinook will look like, which is in that kind of 20%-30% range- Yep, yep ... I think we'll be in really good shape at our lowest dose level. And you continue to see improvements over time with preservation of eGFR, I think we'll be in a really good spot- Yep - at 80. Then we'll have to see what 240 looks like. And- No, absolutely. I mean, in addition, you know, to the proteinuria, also, we're looking across different B-cell phenotypes, as well as serum Ig levels. One of the unique aspects that we saw in the phase 1 was an effect on antibody secreting cells following a single dose. Mm-hmm ... in healthy volunteers, which adds, I think, the story and the depth of the molecule. Yeah. So primarily, the proteinuria in that 20%-30% range is the target. But again, just reminding everyone, this is our lowest dose and a once-a-month regimen, which the once-a-month regimen actually does resonate quite well, and I think it's very attractive for investigators and for patients as well. And just to compare to the comps here, so povetacicept will be given Q monthly. If you look at the wild-type TACIs, they're given Q weekly. Mm-hmm. And the anti-APRIL antibodies are typically given Q two weeks or Q monthly. So, and look, if you bring in any data outside, the most of the patients at ASN will be IgAN patients. Mm. But even a few patients in those other real indications, whether that's LN or PMN, I think will be instructive. Okay. Just back to the healthy volunteer data in terms of, you know, the level of dose response you've seen, maybe just comment on that, and should we think about, you know, 80 milligrams as kind of the low end, and you should see a bump up at 240, or just, you know... Or can we think that way now? You know, I think what we saw in the healthy volunteer trial was more target coverage, right? Okay. And, and also, to Remy's point, antibody secreting cells. So you look at 240, you do, reduce antibody secreting cells a little longer than you do at 80. So there is some thought that at the 240 level, you may see improvements in clinical outcomes, but that's why we do the studies. So we're gonna do 80, and we're gonna see what 240 looks like, and I think based on that data, we'll have a very clear plan going forward on which dose we do going forward on IgAN. Yep. And you mentioned maybe some early data from the other two basket studies at ASN. Just, you know, what are the similar endpoints there, or what endpoints should we be paying attention to? Well, it's part of the same RUBY-3 basket, they're just different cohorts. So we have a high IgAN cohort, which will be where most of the patients come out at ASN, but there's two other glomerulonephritis cohorts in the RUBY-3 study. One is primary membranous nephropathy, and the other is lupus nephritis. The vast majority of the patients that we'll be sharing at ASN will be IgAN patients. On the PMN side, they're very similar endpoints. They're proteinuria endpoints and then also autoantibody reduction. Gotcha. Maybe once we get past the ASN update, you know, what's the next update from the study, or, or have you- Well, I think we should just like... You know, this is our initial update from RUBY-3, right? So there's gonna be a very consistent cadence of news flow coming out of both the RUBY-3 and RUBY-4 baskets- Yep ... for the next 18 months. Right, so you're gonna see-- we're gonna have our initial data at three months on 80, then we'll have, you know, longer term follow-up on the 80-milligram cohort at six and nine months. And then you'll see the same thing from RUBY-3 at 240, three, six and nine-month data coming out of the 240 cohort from RUBY-3. On top of that, you'll start to see our cytopenia data come in. So you'll see the cytopenia basket or RUBY-4 has warm autoimmune hemolytic anemia, ITP, and cold agglutinin disease, and so you'll see data come out of that basket going forward. Yep. Maybe just back to IgAN, and maybe you can talk about the competitive landscape there, and is the goal to be similar, or is the goal to hopefully be better here? Or how do you think about that? Yeah. It's an important space. I think a base case scenario for us is we're similar from an efficacy perspective, but we have a more convenient dosing regimen in an IgAN patient perspective. Yep. From an Alpine corporate perspective, IgAN is one of- Right ... five or six indications that we're interested in. That includes, you know, RUBY-2, which is our lupus interest. It includes, you know, WAHA and ITP, you know, myasthenia gravis. So we're not an IgAN-only company. The, the comps that you're comparing us to are only IgAN companies. We're not an IgAN company. Yep. We're a company that focuses on a number of different autoantibody-mediated diseases, very similar to what the FcRns are doing. Yep. So, yeah, in the IgAN space, the base case is you look similar to them, but with more convenient dosing. Best case is you have better efficacy than them, either at the 80 or the 240 level. Yep. And then, I think with the more convenient regimen, you should be able to own the vast majority of that space. Yeah. I mean, the IgAN space itself is shaping up to be quite an interesting indication on its own. It's a larger market, I think, than a lot of people anticipated. Mm-hmm. We have good validation now from the Novartis Chinook acquisition. But when we talk to KOLs, you know, their primary interest is disease modification, and in particular, the BAFF/APRIL axis being the most interesting part of that. Mm. And so I think that's where a lot of the activity is gonna be, and that's where you'll see a lot of patient interest and I think, KOL interest as well. And within that space, we're gonna be well positioned to- Yep ... to be the best molecule in class. Yep. Can you maybe talk about, the sort of the debate going on, whether you need, BAFF? You know, is APRIL enough? What does BAFF get you? Just maybe the current sort of state of thinking there. Well, I think you can look at where we have data. Yep. Right? And so, obviously, APRIL is an important element, and you're seeing activity from the anti-APRIL antibodies in the IgAN space. But I'd point you to the wild-type TACIs, which are primarily BAFF inhibitors. They do have a little bit of APRIL activity, but they have BAFF, and they're also showing, I think, strong data in the space, about 30% reductions in proteinuria. Yep. So I think you need both pathways in IgAN. And if you look at kind of what's upregulated in IgAN patients, they upregulate both APRIL and BAFF, and they're compensatory pathways. Mm-hmm. You can't target just one and miss the other. Eventually, you're gonna escape, you know, one or the other pathways. Yeah. So the fact that we cover both pathways is very important for us in terms of IgAN. Much more important as you go into diseases like lupus... where there, you know, BAFF is a validated pathway there with Benlysta- Yep being approved. In fact, that we can now go after, you know, lupus indications, and we can go after other autoantibody indications. Yep. You talked about lupus, and I think that's RUBY-2. Yeah. I messed that up again. Yeah. I gotta write this up. A lot to keep track of. That happens to me all the time. Maybe talk about that study a little bit. I think you're waiting for some more data before you decide to sort of start enrolling that. So maybe talk us through that. RUBY-2 is a lupus study that we're highly interested in. The reason we're interested in lupus is obviously BAFF has been validated in lupus as an indication, and there's been emerging data from the wild-type TACIs to show that they've put out very promising data from an Asian population, only particularly from the wild-type TACI that RemeGen has, and with the lupus data look very strong. We believe we have a much more potent molecule than telitacicept, and we definitely know that we cover BAFF in a way that's similar to what Benlysta does, but we add on APRIL on top of it. Mm-hmm. So we think lupus is a very important indication for us that we should be a winner in. We wanna make sure we get the dose right there, so we'll take the learnings from both RUBY-3 and RUBY-4, the two basket studies going on now, to instruct us on what dose we should take forward into RUBY-2. And the goal is to start the RUBY-2 lupus study in the second half of next year, based on what we learned from the two baskets. Can you remind me the dosing in RUBY-3 and RUBY-4? Is it the same 80, 240, or is there something different in four? There's a difference. Okay. So in RUBY-3, which is, you know, glomerulonephritis basket, we started at 80, and then we're escalating up to 240. At RUBY-4, which hasn't enrolled as robustly as RUBY-3- Yep ... we start directly at 240. So we do already have multi-dose experience from RUBY-4 at the 240 level, right? Yep. You know, at 80 level, we've, you know, that went through a safety monitoring committee. They reviewed all that data, and it went on to the 240 level. So the drug is continuing to look very similar to what we saw in our phase 1 healthy volunteer trials, and we think that's gonna be one of those two doses, probably the 80 or 240, that we take forward from here. Mm-hmm. And do you think you'll have a similar dose across the different indications, or could there be slight differences? And then does that make it challenging commercially at all? No. I mean, I think there's a potential that we could have different doses for different indications, and I think- Right ... you know, that could create, you know, certain commercial advantages- Yep for us going forward. Gotcha. Maybe just to try and tie it all together, just, you know, key question we, we hear from investors is just the key points of differentiation for your program. So maybe you could just walk us through those. I know we touched on a lot of them, but... I mean, I can highlight them. I'm sure you're gonna wanna comment on them as well. This is, this is Remy's sweet spot, doing competitive intelligence for us. We're the only true inhibitor of both APRIL and BAFF in development right now. We're giving Q monthly versus Q weekly. Our drug was developed in-house, so we have composition of matter on our IP going out to 2040, with the other drugs in development either have no IP or have IP that's gonna be expiring relatively rapidly. And we're not just developing povetacicept in IgAN, with other glomerulonephritis indications, going after a potpourri of autoantibody immune diseases that we think is gonna create value for, for our shareholders. Yeah, I mean, you hit the differentiation. I think, it's just a different company, you know, it's a different approach when you look at the breadth and the end game. The end goal that we have in mind is so much broader and bigger, and we are building, you know, an immunology company as opposed to an IgAN company. And that's the true focus. Mm-hmm. The reason we can do that is because we have this very potent drug on a very convenient once-a-month regimen that has rationale and support in multiple disease areas that, you know, go within renal, but then also outside of renal. You know, it's a important, important big diseases with big unmet need. I think, just to add on to that, like, as I mentioned in my opening comments, povetacicept was developed in-house through our own discovery platform. It wasn't in-licensed or brought on through an acquisition. And we, through our certain collaborations, like through our collaboration with Horizon, that platform has delivered several molecules to them under that collaboration. We're gonna continue to leverage that. So povetacicept is not the end all... I mean, it's a great drug for us, we're very excited about it, but there's a whole discovery engine at Alpine that's cranking out the next povetacicept across. What we know we can do is create multi-specific proteins that have high potency against well-validated targets, that either improve dosing or improve efficacy or both. Yep. We're gonna continue to leverage our discovery platform to do that, and that's unique. Yep. Uh. So yeah, that's why in the near term, we understand, you know, the focus on IgAN and upcoming readouts, and then looking and having steady catalysts for the next couple of years. That's very important, and povetacicept will deliver on that, but it is a longer, bigger term vision. I think that that's what primarily differentiates us, is the, big vision for the program and the company. Yep. Maybe just back to povetacicept. Mitchell, you sort of mentioned some preclinical data in MG, I think it was. Yep. Maybe you could just talk a little bit about what you saw there and why that's interesting? Yeah. What we saw in that model, it's a standard EAMG model that's used for myasthenia gravis. Essentially, we saw a very rapid improvement in disease scores versus a control, in parallel to reductions in immunoglobulin levels, as well as B cell populations. So very consistent with what we've seen, previously for other indications. Across the board, you know, something we didn't mention on differentiation for BAFF and APRIL versus one alone is. In every model we run, you know, we always see better activity, for dual inhibition of BAFF and APRIL, and in particular with povetacicept- Mm-hmm. versus blockade of either pathway alone. Yep. So then circling back to MG, you know, that's an area we're very interested in. We've shown one disease model, we've presented that at ANA. We're working on, you know, following up on that with additional work and, you know, look forward to discussing that more in the future. MG is a rational indication for us. It's an autoantibody mediated disease. It's obviously a large market. You know, the existing FcRns there have been remarkable in what they've done for the space, but there's liabilities associated with them, either in terms of albumin or cholesterol levels. Mm-hmm. If we can come in with a once-a-month subQ formulation given through an auto-injector, that could be a huge win- Yeah For us in MG, particularly, you know, as we'll continue to look at how we compare against FcRn and other molecules in the MG space. So... Just in terms of the strategy, you know, moving beyond your current two basket studies and your SLE study, and obviously, there's lots of things to choose from, you know, how do you just, how do you think about that? When could you maybe start another phase II study, or is it, let's hold off on that till we kinda turn the cards over on our current studies, or? Yeah. I think IgAN is one that is, like, right at the top of the list. Yep. The endpoints are so clear- Yep - and the regulatory pathway is so pristine, that I think if we can show that, you know, we have deep reductions in protein early on at the 80 dose, we're gonna move very rapidly to push that into pivotal studies as fast as we can. Yep. We won't be far behind what's already in development. In terms of what are the indications we wanna go after beyond that, it may be another renal indication- Mm-hmm - coming out of the RUBY-3 basket, so we'll see what some of that early data looks like. And then we prioritize it based on where the biggest unmet medical need is. That's our top priority. That could be in diseases like, WAHA, for example, or, obviously, SLE is gonna be near the top of the list as well. Gotcha. Maybe just talk about your thoughts on, you know, potentially partnering in the future. Is that something you're considering? What does that look like? Is it indication specific? When would that happen? Yeah, so our thoughts on partnering is to take it to be open-minded. Yep. But this is our core asset, and it would have to be a tremendous collaboration for us to really wanna partner up povetacicept right now. I'm not saying it won't be done, because there's always a deal that can be done, but it would have to be a tremendous deal for Alpine to consider, just given how the molecule looks and how it's behaving right now. Yep. We know it's a very important asset. Yeah. Now, you could do small geography type deals that, you know, could be beneficial for us for a variety of different reasons, but keeping the core markets is something that is really important to us. Yep, makes sense. That's your domain, I mean, I'm sure. Yeah, I think that's accurate, for sure. I think that doesn't mean we're not in dialogue, you know, with pharma. I think it's always... We're constantly talking to different, you know, pharma groups to make sure that they're aware of what we're working on, that we understand what they're interested in, of course. But as Mitchell said, this is really the crown jewel of the company. Yep. Partnering is certainly not a priority, right? Yep. No, it makes sense. Maybe just last question here, if you can talk about your current cash position and what the runway looks like from here? Yeah. We're fortunate that we had a deal led by Morgan Stanley last December, so I'll give you a little plug there. And so we're sitting on about $240 million of cash on our balance sheet right now. We've guided that that takes us out through 2025. And so it, it gives us the flexibility to be very aggressive about how we push forward beyond that. Okay, great. We're just about out of time, so why don't we end it there? Thanks, Mitchell and Remy. Appreciate your time today. Thanks, Michael. Appreciate it. Thanks for having us.