All right. Good afternoon, everyone. Thanks for joining us here at the SVB Securities Global Biopharma Conference. My name's Tom Smith. I'm one of the senior biotech analysts here at SVB, and excited to welcome our next presenting company, Alpine Immune Sciences, and very happy to introduce Chief Business Officer, Remy Durand. Remy, thanks for joining us. Great. Thank you, Tom and SVB for the invitation to present here at the conference this year. Thank you to everyone listening in on the webcast. As Tom mentioned, my name is Remy Durand, and I lead Investor Relations, Business Development, and Corporate Strategy for Alpine Immune Sciences. Today, I'll be making forward-looking statements. Please consult our website for a full list of SEC filings. At Alpine, we're leading the next evolution of immunotherapies for autoimmune disease and inflammatory disease with two compelling molecules, both developed from our highly productive directed evolution platform. Povetacicept, or ALPN-303, is our lead wholly owned program, and it's a potentially best-in-class approach to blocking two key clinically validated B cell cytokines that we're developing for B cell mediated autoimmune and inflammatory diseases. We presented phase I data at our R&D day last year and across multiple scientific meetings in the fall, demonstrating a clean safety profile, compelling reductions in immunoglobulins and other biomarkers, and a best in class dosing regimen. Based on these encouraging clinical and non-clinical data, we're planning a broad development plan with multiple clinical studies, including basket studies in autoimmune glomerular nephritides and autoimmune cytopenias, as well as a phase II study in lupus. Each of the indications we selected has strong scientific rationale for povetacicept based on the importance of specific autoantibodies in disease pathogenesis, as well as high unmet medical needs in each. Acazicolcept, or ALPN-101, is a first in class dual costimulation antagonist for autoimmune and inflammatory disease targeting T cells. In 2020, we announced a transformational option and license agreement with AbbVie around this program, which is currently enrolling an international phase II study in lupus. To date, we've received $105 million in upfront and development milestones, milestone payments. First, let's dive right into povetacicept. This is a molecule with a highly compelling profile for which we're launching a broad development program in multiple indications this year. As a reminder, povetacicept is a dual inhibitor of two B cell cytokines, BAFF and APRIL, that has been engineered specifically for high affinity against both these targets and has demonstrated superior efficacy in preclinical studies in comparison to other tested inhibitors of BAFF and/or APRIL. Povetacicept, we believe, is the only truly potent inhibitor of both BAFF and APRIL. We've conducted a first in human study in healthy volunteers. The results are highly encouraging. The well-tolerated safety profile and dose-dependent PK and PD, including reductions in immunoglobulins and other biomarkers. Importantly, the drug may be administered subcutaneously or intravenously and based on our current PK/PD modeling at least every four weeks. These data enable us to now advance povetacicept into multiple B cell and autoantibody related diseases, including systemic lupus erythematosus, glomerular nephritides, and autoimmune cytopenias. APRIL and BAFF are compelling targets because their dual inhibition may lead to potentially superior outcomes for patients. The two cytokines play complementary and partially overlapping roles in B cell development and activation as illustrated in this figure, which depicts the expression pattern of their three receptors during B cell development. Early on, BAFF plays a dominant role related to BAFF receptor expression, while later stages are APRIL and/or BAFF dependent related to TACI and BCMA expression on B cells. It's important to note that APRIL and BAFF responsiveness continues well into the B cell stages that produce antibodies, and in particular plasmablasts and plasma cells, which are often considered the dominant source of the pathogenic autoantibodies in lupus and other related diseases. Receptors such as CD20, the target of rituximab, are poorly expressed in plasmablasts and plasma cells, suggesting a unique target differentiation versus BAFF and APRIL. The clinical rationale for developing povetacicept is that BAFF and APRIL are clinically validated targets thought to play key roles in a number of diseases. This has been observed first from data from BENLYSTA, which targets only BAFF and is approved in lupus and lupus nephritis. More recently, Regeneron wild-type TACI molecule, telitacicept, showed highly encouraging results in a lupus phase III study and has received conditional approval in China. In povetacicept, our scientists have engineered a next generation variant of the TACI receptor that acts as a potent inhibitor of both BAFF and APRIL and has best in class potential as evidenced here on the subsequent slide. The engineering of povetacicept was focused on increasing the affinity of TACI against both BAFF and APRIL. APRIL was of particular interest because wild-type TACI appears to be a relatively weaker inhibitor of APRIL. Here, the sensograms of surface plasmon resonance analysis are shown. In this case, using commercial telitacicept as a source of wild-type TACI. I wanna draw your attention to the lower right panel here, showing that while wild-type TACI does bind APRIL, it appears to have poor retention, and APRIL falls off relatively rapidly. In contrast, povetacicept demonstrates significantly improved retention, very similar to what you might expect from a high-affinity inhibitor like an antibody. Overall, povetacicept appears to have improved the affinity of TACI against BAFF 8-10-fold and dramatically improved the affinity against APRIL. These attributes correlate with significantly improved efficacy in multiple preclinical models. For instance, in a sheep red blood cell challenge model on the left, povetacicept in green has the most potent effect upon antibody responses, as well as plasma cell formation compared to wild-type TACI in blue, single inhibitors of BAFF or APRIL in orange or red, or even the combination of the two BAFF and APRIL specific biologics, which is in purple. These types of studies demonstrate that inhibition of BAFF and APRIL is likely required in many target diseases since they can have non-overlapping functions. Furthermore, povetacicept similarly exerts potent efficacy in the New Zealand lupus model, suppressing key markers of disease, including anti-DNA antibodies, nephritis, and proteinuria, as well as salivary gland inflammation or sialadenitis. Based on these and other non-clinical data, we advanced povetacicept into a phase I study in healthy volunteers, the design of which is shown here. RUBY-1 is a first-in-human study of povetacicept in healthy adult volunteers. It is a single ascending dose study exploring both intravenous and subcutaneous routes of administration, as shown on the left. Endpoints of particular interest besides safety include pharmacodynamic effects on circulating immunoglobulins since prior drug candidates have published benchmarks thereof. Circulating B cells were also of interest. Prior candidates have not reported reduction in B cell populations when administered as single doses to healthy adults, but they are of interest with povetacicept since they were observed preclinically and may provide additional biological differentiation. Moving on to the clinical data, overall povetacicept has been well-tolerated. There is a slight numerical excess of adverse events in the povetacicept subgroups, although mostly grade 1. Importantly, no administration-related reactions were noted, except mild injection site pain, and there were no severe infections or severe hypogammaglobulinemia. povetacicept demonstrates dose-dependent pharmacokinetics as shown for the IV doses on the left and the subcutaneous doses on the right. The 80 mg and 240 mg dose levels are of particular interest as we anticipate these to be the primary phase II doses. In both cases, the bioavailability appears favorable. povetacicept also exerts dose-dependent target coverage as assessed by circulating free APRIL levels. Note that at 240 mg in green or higher, free APRIL is essentially completely suppressed throughout the four-week observation period. 80 mg in red is also effective for at least two to three weeks. Interestingly and importantly, povetacicept exerts dose-dependent effects upon circulating B cell subsets, particularly the antibody-secreting cell CD38 high plasmablast plasma cell subset within the memory B cell population. This is of particular note since, as previously mentioned, this population is thought to contribute significantly to pathogenic autoantibody production in various diseases, and to our knowledge, has not previously been reported by other BAFF and/or APRIL inhibitors, at least after single doses in healthy adults. povetacicept also exerts dose-dependent effects upon circulating serum immunoglobulins. In slide 16, we've compared povetacicept's effects with those previously seen with wild-type TACIs and the anti-APRIL antibodies. These graphs all show 80 mg subcutaneous povetacicept, now in green, and the placebo comparator from the RUBY-1 study in black. Each of these columns overlays published data from the confirmed or anticipated pivotal doses of four different comparators, atacicept and telitacicept on the left, and two clinical stage APRIL antibodies on the right. It's notable that povetacicept appears to result in greater IG reductions than tacicept or telitacicept versus comparable or perhaps even slightly greater IG reductions versus the APRIL antibodies. Overall, these findings suggest two things. One, APRIL appears to play a more dominant role than BAFF in circulating IG levels, at least in healthy adults. Two, the observations with povetacicept are consistent with its improved APRIL activity compared to wild-type TACI. In addition to showing reductions in IgA, IgG, and IgM on the previous slide, we recently presented data at the American Society of Nephrology Kidney Week 2022 demonstrating that povetacicept dose dependently reduced Gd-IgA1, an important effector molecule and biomarker in IgA nephropathy, which is in one of our basket studies. Notably, the effects on Gd-IgA1 reduction were comparable to those observed with anti-APRIL antibodies in healthy volunteers, consistent with the data on the last slide. Overall, the encouraging pharmacodynamic effects, including dose-dependent reductions in free cytokine, circulating immunoglobulins, and antibody-secreting cells, including Gd-IgA1, support therapeutic doses to be in the 80 mg to 240 mg dose range, and importantly, administered subcutaneously every four weeks, which is a major differentiator for the program. We believe povetacicept has a potential to become a pipeline end product with significant market opportunity across multiple diseases, including, but not limited to, renal, hematology, and rheumatology. Based on our encouraging clinical and non-clinical data, we are initiating a broad development plan with multiple studies, including RUBY-3, an open-label dose-ranging basket study in autoimmune glomerular nephritides, which includes IgA nephropathy, lupus nephritis, and primary membranous nephropathy. It also includes RUBY-4, an open-label basket study in autoimmune cytopenias, which includes immune thrombocytopenia, warm autoimmune hemolytic anemia, and cold agglutinin disease. In addition to RUBY-3 and RUBY-4, we plan to initiate RUBY-2, a placebo-controlled dose-ranging randomized phase II study in systemic lupus as soon as possible based on interactions with appropriate health authorities. Altogether, we anticipate that the basket studies will provide significant insight into povetacicept's activity in the near term while the lupus study is initiating and enrolling. Each of these indications also has its own medical need and development rationale as well, many of which include potentially accelerated and/or highly efficient development plans. We therefore anticipate potentially pursuing one or more such accelerated approval pathways, likely based upon discussions of our data with and guided by health authorities. In summary, povetacicept is a potent dual inhibitor of the BAFF and APRIL cytokines. We think it could be best in class based on the preliminary non-clinical and phase I data we presented, which demonstrate it to be well-tolerated with potent on-target effects on circulating Ig and antibody-secreting cells, enabling a convenient dose regimen. We are looking forward to initiating a broad development plan that is about to be launched in multiple therapeutic areas. Shifting from focus from B cells to T cells, let's touch on acazicolcept, which is our dual costimulation antagonist broad immune disease. CD28 and ICOS are two important costimulatory pathways on T cells responsible for driving both T cell activation and proliferation. This makes them attractive therapeutic targets for autoimmune and inflammatory diseases, where T cell activation is thought to play a major role. Approved therapies, however, only target the CD28 pathway, leaving the ICOS pathway available for signaling and exacerbation of disease. In contrast, acazicolcept was engineered to inhibit both of these critical pathways, targeting both naive T cells expressing CD28 and differentiated T cells expressing ICOS, with the overall goal of creating a single molecule to produce vastly improved patient outcomes. The compelling preclinical data generated for acazicolcept and a phase I study demonstrating that acazicolcept was safe and well-tolerated generated significant partnering interest, and we were pleased to announce a transformative option and licensing agreement with AbbVie in June of 2020. As has been previously disclosed, terms of the agreement include a $60 million upfront payment and $805 million in downstream milestone payments. Importantly, as part of the agreement, there are $75 million in potential pre-option milestone payments, $45 million of which were achieved with the start of DENALI, our phase II study of acazicolcept in lupus. Lupus has long been a compelling target indication for acazicolcept. Not only is it a potentially life-threatening multi-system chronic autoimmune disease with few approved treatment options, but the CD28 and ICOS pathways specifically have been increasingly recognized as contributing to disease pathogenesis. Our phase II study in SLE called DENALI is evaluating acazicolcept versus placebo in 130 patients over six months. The primary endpoint is safety. However, we will also be measuring key secondary endpoints, including efficacy and changes in biomarkers. From a corporate perspective, Alpine is well-funded with $290 million in cash following a productive 2022, which included a successful $113 million follow-on offering with top-tier investors in October to further accelerate development of povetacicept in multiple indications and which extends our cash runway through the end of 2025. To summarize, we are looking forward to a highly productive 2023 when we will initiate a broad development plan for povetacicept. We are particularly excited to initiate our open-label basket studies in glomerular nephritides and autoimmune cytopenias, as they should provide a rapid assessment in multiple diseases and may potentially enable multiple accelerated development paths. We are targeting to report initial preliminary data from these basket studies by the end of the year. Alpine is led by a strong management team with deep experience across key functional areas and supported by a blue-chip board of investors and operators. With that, I'd like to thank you and open up the line for any questions. Great. Thanks, Remy. Yeah, appreciate the overview. You covered a lot of ground, and you guys certainly have a lot going on, not the least of which is, initiating the RUBY-3 and RUBY-4 basket studies. Maybe if you could just expand a little bit on some of your comments. You know, among the indications that you're looking at in that sort of basket format, can you talk to, I guess, how you think about kind of probability of success and which indications you're more bullish on? I guess, yeah, let's start there. Sure. You know, I think part of the rationale for developing povetacicept was the fact that these targets are now very well clinically validated on, you know, first, as I mentioned, with BENLYSTA and the BAFF target and APRIL as well, through the anti-APRIL antibodies. You also have data from RemeGen with their wild type TACI. I think from a data validation perspective, you know, Lupus is obviously a very, you know, clear place for us to go, and it was the initial anchor indication we've identified. Really, you know, the indications we've focused on are those that are mediated by autoantibodies and that have these clear biomarkers. In terms of probability of success, you know, I think you look at IgAN as well as an area where there's a wealth of data for this mechanism that implicates the role of BAFF and APRIL as well. You know, even beyond just looking at BAFF and APRIL, indications where rituximab has had some efficacy typically in an off-label setting, those are highly appealing to us, and that would include indications like primary membranous nephropathy, lupus nephritis as well. It's important even to shift outside of renal and into the cytopenia baskets too. You know, this is an area where we've become increasingly interested, and we really do view the potential of this program more in line with the size of the opportunity for FcRns, right? What you've seen with argenx and Momenta's J&J program, which leads us to the ITP and the autoimmune hemolytic anemia opportunities where there's a bit less data there for the BAFF APRIL target itself, but there's an opportunity for us to be first in class. Given that these are mediated in large part by autoantibodies, we're excited to move into these, get the basket data up and running, and see, you know, how povetacicept can impact this disease, improve outcomes, ideally improve outcomes well beyond with what we're seeing from existing therapies, include the FcRns. You know, again, just to get back to your question and try to answer it more succinctly, I mean, lupus, you know, we do feel is a very high probability of success based on the data. There is then a wealth of data in the kidney indications, IgAN and LN, and then just based on rituximab and BAFF APRIL there. The cytopenias are highly interesting, and even outside of that, there's data in myasthenia gravis as well as dermatology indications where autoantibodies are clearly playing a role. RemeGen's molecule has some data in myasthenia gravis again, so that's an area of interest for us. Just road mapping out, you know, where we are now versus where we wanna be in several years, I think that's where you see the opportunity start to grow. Yeah. Okay. Yeah, I think that makes a lot of sense. I wanted to come back to... I mean, you mentioned IgAN and kind of the growing body of data we have there and, you know, recently we saw data from a, I guess kind of first gen BAFF APRIL antibody, atacicept, where you saw a signal there, I think it was around the 33% mean reduction in proteinuria out to week 24, but what seemed to fall short of some of the other competing compounds that are in IgAN, specifically the APRIL-specific compounds. I guess, you know, I'd love to get your view on that data set and, how you think that kind of plays through to what you guys are doing with, povetacicept. Sure. No, it's a very good question, you know, one we've gotten, of course, from investors and folks as well. You know, although the caveat being here, you know, it's very hard to compare across trials, of course, and these are two different trials and, you know, patients with different entry criteria and factors like that. You know, I think from our view, this data played out fairly well as we would expect it. As we've shown in our slides, at least in the case of telitacicept and the wild type TACI is, you know, we do view the first generation molecules as largely mostly blocking BAFF. What the data from the molecule you referenced highlights is actually that BAFF plays an important role in IgAN, and that we have seen the data from Chinook's molecule in APRIL. I think what this first-gen molecule shows is that BAFF plays an important role as well, but it may be the case that the added APRIL inhibition gives deeper and potentially more sustained responses in proteinuria than you might get with BAFF alone. That gets to us for the rationale of having dual BAFF APRIL inhibition, is it's important to cover the entire spectrum of B cell development, such that with the APRIL inhibition, you're likely seeing a more rapid, potentially deeper response. Over time, we would expect that the added inhibition of BAFF that we get with ALPN-303 and the APRIL inhibition will give ideally more sustained, more disease-modifying results as you're covering the entire B cell spectrum. Got it. That makes a lot of sense. Okay. I also wanted to ask about, you know, one of the takeaways from the phase I healthy volunteer experience has been kind of the nice PK/PD profile. Mm-hmm ... that you guys have, and it does seem to set up a pretty favorable dosing regimen. All other things being equal, even on efficacy and safety tolerability, maybe if you could just speak to, you know, based on the research you guys have done, maybe some of the market research that you're conducting, how important is the less frequent dosing in some of these indications like a lupus or an IgAN? Yeah, it does depend. I'd say, you know, what we've found so far is that efficacy does trump, right? Physicians do want the drug that's most efficacious. After that, you know, and of course safety as well, that's table stakes. After that, we are seeing the dosing regimen in particular, in settings where IgAN, you know, you have younger patients, you have patients that are dosing at home. Having a convenient subcutaneous administration that's dosed, Q4 weekly or once a month, that is viewed as more favorable than a weekly or biweekly approach. I would say, you know, we screen early on in our platform for molecules that are well-behaved and developable in addition to those that are highly potent. We set out from the beginning to build an overall drug product that was appealing from both a potency, safety, efficacy, and dosing perspective. You know, right now we're at a Q4 weekly regimen, Q4 weekly, and then we'll continue to explore if we can even make that less frequent. But that's, I'd say, early stages still. Our early market research says, you know, in indications like even lupus where you have a younger population as well, and IgAN, or patients that are at home, they're relatively healthy on a day-to-day, having a Q4 regimen is important. Got it. Okay. Yep, that makes sense. Let's come back to the basket studies and, I guess specifically, again, kind of thinking through each of the indications that you've walked through. Yeah. How do you think about patient enrollment, I guess, into each of those? Just help us kind of think through the potential cadence for data updates here? Yeah, absolutely. You- Absolutely. Right now, what we're guiding towards is that the RUBY-3 renal autoimmune glomerulonephritis study will likely get up and running first, and that, you know, based on prevalence alone, for IgAN, you might expect that you would see greater enrollment in IgAN. That being said, we are just getting enrollment started and so We're getting the studies initiated, so we do wanna wait and see how enrollment looks across the various sites. You know, we're taking a very kind of broad approach to enrolling sites and building relationships with KOLs because as you know, this is a competitive space. The goal is to have initial data that we can share later on this year, and typically, as we would do, prefer to share that data at a scientific forum as we've done in the past. Again, you know, probably looking at a greater enrollment on the RUBY-3 side first, potentially more IgAN patients just based on prevalence, but I don't wanna give too much guidance there as we wanna get enrollment going first. Then on the RUBY-4 side, ITP side, in similar situation where you have a higher prevalence of ITP, so we may expect more ITP patients relative to the others for that initial data look. I do wanna remind everyone that the goal of the basket studies is to have an MAD experience early, see early signs of activity in patient populations. Once we have sufficient data from those basket cohorts, you know, our plan is to use those as a bridge to get into phase II studies, some of which could even form the basis of pivotal studies down the road. We really think about these basket studies as that bridge to dedicated phase IIs in specific indications. Right. Okay. Makes sense. Yeah. No, I like the way that you've designed this and laid out with very objective endpoints that can be evaluated in open label setting that get you to an answer relatively quickly. Exactly. In these cases, you know, there's a biomarker typically that correlates well, like in IgAN, in ITP, we can track platelet counts early on. These provide these numerical quantitative measurements that we can see early and then track over time. Right. Okay, great. Just, I know we're coming up against time here, but just, if you could also mention, I know you have preclinical collaborations with the likes of Horizon and Adaptimmune. We do, yeah. Just kind of highlight, I guess, what kind of preclinical work you're doing there and whether we can expect anything to emerge from that over the next 12 months. We have a great collaboration ongoing on the discovery immunology side with Horizon Therapeutics. That program involves up to four targets. Again, we haven't disclosed what those targets are, and we can't say for certain where the news flow is coming or to be honest, you know, the situation with Amgen here. I can say that again, the collaboration is focused on novel targets, against multiple, typically pathways within the immune system, on the discovery side. And importantly, you know, Horizon does cover our FTE and our discovery costs there. That collaboration is going very well. We really like the molecules that are being developed there, so you know, I think, we're happy with how that collaboration's going and would be happy with the direction it takes, you know, I think either way. On the Adaptimmune side, of course, you know, we've shifted away a bit from the oncology and are focused on immunology. I think not too much else to say, but that collaboration is still ongoing though, and we are excited about the potential there in the setting of TCR T cell based therapy using our discovery programs there. Got it. Okay. That makes sense. Yeah, we'll stay tuned on, on both of those. Unfortunately, yeah, we're up against time, Remy. It's good. Appreciate you joining us and walking us through the story and providing the updates and looking forward to the basket study initiations and data hopefully by the end of this year. Yeah. Thank you, Tom. Great questions, and thank you everyone for listening in. Have a great day.