Good morning. Welcome to the 42nd annual J.P. Morgan Healthcare Conference. My name is Edwin Zhang. I'm a member of the J.P. Morgan Healthcare team and your moderator for this session. Today, I would like to introduce you to the team from Alpine Immune Sciences. Please join me in welcoming our presenter, Mitchell Gold, who is the Chairman and CEO of Alpine. Thanks, Edwin. I would like to remind you that I will be making forward-looking statements during the course of my presentation today, and I encourage you to refer to the most recent SEC filings regarding the risk factors associated with these statements. Since our founding, Alpine has been passionate about using our directed evolution platform to create novel protein structures and novel molecules that could dramatically transform healthcare and improve patients' lives suffering from debilitating diseases. We believe we've accomplished that with povetacicept. Povetacicept represents a best-in-class opportunity, inhibiting both two central B-cell cytokines, APRIL and BAFF, and it's administered in a once every four-week dosing regimen, given in a low volume, less than a half of an ml injected volume every four weeks. Our phase 3 data... Or excuse me, our data presented at the American Society of Nephrology meeting in November represented a best-in-class profile for this drug with deep proteinuria reductions, and based on that data, we anticipate moving into a phase 3 study in the second half of this year. Beyond IgA nephropathy, we have a broad potential for moving povetacicept in a number of different indications, and we'll be exploring those throughout the course of the development plan for povetacicept that I'll talk about in just a bit. 2024 will be a catalyst-rich year for the company, and I'll highlight some of the key milestones occurring throughout the course of this year. Because povetacicept was developed internally, it's wholly owned. We don't owe any third-party milestones, and we don't have any third-party royalties. In addition, we have composition of matter intellectual property out to 2041, with the ability to extend it beyond that. Based on the financing we did in November of last year, we're sitting on a strong cash position, which allows us to prosecute a very broad development plan for povetacicept. Povetacicept is an engineered version of wild-type TACI. It's an Fc fusion protein. Specifically, we engineered Povi to overcome some of the limitations of wild-type TACI itself. Principally, what we engineered povetacicept to have was higher APRIL affinities than wild-type TACI. In addition, we overcame some of the limitations of dealing with dosing. Specifically, we were able to go from a Q one-week dosing regimen with the wild-type TACIs to a Q four-week dosing regimen with povetacicept. Based on the strong affinities against APRIL and BAFF, we're able to move povetacicept in a number of different indications. So we have a very broad development plan. We see povetacicept as being a pipeline and a product. In addition to pursuing IgA nephropathy, we're gonna be launching a phase 3 study in that in the second half of this year. We'll also be launching a phase 2 study in systemic lupus, generalized lupus, in the second half of this year. We'll glean additional data coming out of some of our open label basket studies throughout the course of this year. RUBY-3 is an open label basket study looking at a number of glomerulonephritis indications. In addition to that follow-up data in IgA nephropathy, we also expect to get data throughout the course of this year in primary membranous nephropathy and lupus nephritis. Then we have a cytopenia basket study called RUBY-4, which is looking at a number of different cytopenias, including warm autoimmune hemolytic anemia, ITP, and cold agglutinin disease, and we expect to have data from that basket study in the first half of this year. So we specifically engineered povetacicept, as I mentioned, to overcome some of the limitations associated with the wild-type TACI. Our team had deep experience in developing wild-type TACI proteins, and they knew that one of the main limitations of that was the limited APRIL binding associated with the wild-type TACI development programs. Povetacicept, as you can see from this cell-based assay here, povetacicept at the top, has antibody-like affinities against the APRIL axis and has similar potencies against BAFF to the Benlysta and the true BAFF inhibitors. So we believe we're the only true potent inhibitor of both APRIL and BAFF, and povetacicept was specifically engineered to improve its APRIL binding and improve its dosing schedule. When we studied povetacicept in a number of different preclinical models, what we saw was that povetacicept consistently outperformed existing treatment options for these diseases. So in a preclinical model of lupus nephritis, hemolytic anemia, and autoimmune myasthenia gravis, povetacicept outperformed wild-type TACI proteins, as well as anti-CD20s and ofatumumab. We then moved povetacicept into a phase 1 healthy volunteer trial called the RUBY-1 study. That was an important study for the company because what it showed was that povetacicept, one, had significant pharmacodynamic effect. It dropped Ig levels substantially, and it confirmed that we were able to achieve a Q4-week dosing regimen with povetacicept. So this study really was central for us when we, when we embarked on the journey of Povi to create a Q 4-week dosing schedule, to have a drug that improved its APRIL binding. It was the first phase I study that we did that really confirmed that effect. So those two dose levels, both the 80 and 240 milligram dose levels, are the principal dose levels that we're taking forward in our studies going forward. So a little bit about where we sit with povetacicept today. Povetacicept is in two open-label basket studies currently. One is called RUBY-3, which is our open-label glomerulonephritis basket study. It's enrolling three different glomerulonephritis subtypes: IgA nephropathy, primary membranous nephropathy, and lupus nephritis. The primary patients that we've enrolled into this study are the IgA nephropathy subtype patients. So a little bit about IgA nephropathy itself. IgA nephropathy is the most common glomerulonephritis globally. It's caused by an aberrant glycosylation of IgA. When you get this aberrant glycosylation of IgA, it causes an autoimmune response, and those immune complexes then get deposited in the kidney, where they cause inflammation and result in end-stage kidney disease. Unfortunately, this disease occurs in patients that are relatively young, in early adulthood, and many of these therapies progress, 50% of these patients progress to renal failure within 10 years. There's really no current therapies that address the underlying disease. Either patients are put on steroids or they're, they deal with the causes of proteinuria, but no current approved treatment options deal with the fact that there's autoantibodies being directed against the aberrant glycosylated IgA1. So the promise of povetacicept and the ability to inhibit both APRIL and BAFF gives us the ability to really address the underlying cause of IgA nephropathy. The reason that's important is if you can address the root cause of the disease, you can really dramatically improve the cause, the outcome of patient care. There's about 125,000 patients in the US that have this disease, about 265,000 patients globally. This is a, you know, big indication for us to go after. As I mentioned, about 50% of patients will progress to renal failure within 10 years of outcome. There's really strong mechanistic rationale to think about why APRIL and BAFF are important in addressing IgA nephropathy. When you look at IgA nephropathy patients, both APRIL and BAFF are upregulated in this patient population. In fact, if you create a BAFF transgenic animal, they'll spontaneously generate IgA nephropathy like glomerulonephritis. And there's been encouraging data coming out from a number of different molecules in the class. Both the anti-BAFF and pure anti-APRIL antibodies have shown interesting outcomes on proteinuria reduction and eGFR stabilization, and then some of the wild-type TACIs themselves has begun to report early data in IgA nephropathy. We believe povetacicept represents potentially a best-in-class program, giving its deep reductions in proteinuria and its Q4-week dosing regimen. So let me walk you through a little bit of the RUBY-3 study and the data that was presented at the American Society of Nephrology meeting in November. The RUBY-3 study was an open-label dose escalation study. It enrolled three different, patient subtypes, as I said, PMN, LN, and IgA nephropathy, and we've studied povetacicept to two different dose levels, both the 80 milligram dose level and the 240 milligram dose level. The data that we reported out at ASN, I'll share with you in just a bit, but I'm pleased to report that at the 240 milligram dose level, given the investigator enthusiasm that we saw coming out of ASN, that dose level now has exceeded the number of patients that we saw at the 80 milligram dose level. So enrollment continues to be very strong and robust, and there's deep investigator interest in having programs like APRIL and BAFF to use for patients that are suffering from this disease. What I didn't mention earlier is that physicians see these programs, the ability to really get to the underlying root cause of disease, as being used as frontline treatment for these patients. The baseline characteristics from the RUBY-3 study that were presented at ASN were very typical of other studies in the IgA nephropathy space. Patients had a 24-hour UPCr of about 1.3 and an eGFR of about 70, and the median age was about 51 years old. Importantly, povetacicept was extremely well tolerated in this study. There were no serious, grade 3 or grade 4 adverse events, and there were no injection site reactions reported. So one of the measurements that's very important in patients with IgA nephropathy is looking at UPCr, the urine protein to creatinine ratio, and that's an important predictor of overall renal function, and it's an endpoint that can be used for accelerated approval in this disease. Importantly, the depth of proteinuria reduction, so how deep your proteinuria gets reduced, correlates directly with clinical outcomes and renal benefit. So the data that we presented at ASN at the six-month time point was the deepest proteinuria reduction that had been reported to date, a 53.5% reduction in proteinuria at six months. In addition, what I'm pleased to report is we've had a couple more patients come through at that six-month time point, and that data continues to hold true. So that data is being stable. Even though more patients are coming through at that six-month endpoint, the data continues to look consistent with what we've seen previously. You know, as we're making progress in the field, we're now starting to consider an important concept of remission. I think this was something that seemed very elusive historically but now is becoming a reality. So there's different concepts being floated around about how you would define remission. We define remission with a very strict set of criteria, a UPCr of less than 0.5 grams per gram, and you had to have a UPCr reduction of more than 50% or greater from baseline, and you had to have a stable eGFR. So when we applied all three sets of these criteria, not just one... Sometimes you'll see just proteinuria reductions being used as remission criteria. When we applied all three sets of this criteria, we had one patient that achieved that remission criteria at three months, but 80%, four of the five patients that we reported out, had 80% remission rate at six months. So this is something that's very encouraging to us. I think it's a testament to the fact that we're able to potently inhibit both APRIL and BAFF, and I think it's a testament to the class of how important that is to inhibit those two B-cell cytokines for this disease pathway. One of the key biomarkers in IgA nephropathy is galactose-deficient IgA1. And when we looked at how povetacicept reduced galactose-deficient IgA1 in this study, we reduced galactose-deficient IgA1 by about 60% in this patient population. And importantly, the key central measure of renal function is estimated glomerular filtration rate. When we looked at eGFR, we either had stabilization or slight increases in eGFR from the data that was reported at ASN at the 80-milligram cohort. We did have a significant effect on reducing Ig. In fact, we reduced all Ig subtypes. So we reduced IgA, IgM, and IgE. This is the first reported instance that we know that IgE was reduced with a dual APRIL-BAFF inhibitor, and that gives us, you know, a little bit of a thought about pursuing IgE-mediated diseases potentially downstream. Because we see Alpine as not just being a company that's going to develop IgA nephropathy therapies, but we want to really take povetacicept to the next level and be a pipeline hitter product. So I'll talk about that just in just a bit. One thing I want to highlight for you is the IgG levels. So the IgG levels here, you can see, are dropped by about 20%-25%. And IgG, obviously, is a protective autoantibody. But one of the unique features of inhibiting APRIL-BAFF is it seems to preferentially target pathogenic B-cell clones, as opposed to protective B-cell clones. So the overall IgG is being preserved. This is in contrast to what you'd see with the FcRns, for example, where we're able to target pathogenic IgG more specifically, and I'll show you that in just a bit. So this is a case study that we had that was presented at the American Society of Nephrology meeting in November. It was a patient that had primary membranous nephropathy, and you can see here that the patient had relatively high titers of an IgG autoantibody called anti-PLA2R1. When the patient received povetacicept, you can see they had a 99% reduction in their pathogenic autoantibody, anti-PLA2R1. But as you recall from the previous slide, we're able to preserve protective IgG. So there's something about inhibiting APRIL and BAFF that allows you to target the more pathogenic B-cell clones and preserve IgG itself. So in summary, we believe povetacicept represents potentially the best-in-class opportunity for patients with IgA nephropathy. It's showing the deepest reductions reported at six months, with a greater than 50% improvement in UPCr and greater than 60% reductions in Gd-IgA1. We are seeing evidence of early remissions, and this is something that we'll continue to track. So based on that data, we're gonna move povetacicept directly into a phase 3 study in the second half of this year, and then we're gonna continue to explore povetacicept across a number of other indications that I'll talk about in just a bit. I can't emphasize enough that povetacicept was well-tolerated, and the profile of povetacicept is exactly, I think, what these patients are looking for: a once-a-month dosing regimen and a low volume of injectate. Think about 0.4-0.5 mL of injectate volume that can be delivered through an auto-injector is gonna be highly appealing from a commercial setting for patients. So our two central focuses over, over the next year are really to operationalize studies in both IgA nephropathy and systemic lupus. As I mentioned, there's about 265,000 patients globally with IgA nephropathy. Our goal is to begin a phase 3 study in the second half of this year with povetacicept. In terms of SLE, our plan is to start a placebo-controlled phase 2 study in the second half of this year, really exploring the potential of povetacicept in that indication. While we're operationalizing those studies, we'll be thinking beyond those two indications to, for potentially other indications. So we'll get data from the RUBY-3 basket, from the other glomerulonephritis indications that I mentioned, both PMN and lupus nephritis, and we'll use that data to drive our development plan going forward. Plus, we'll receive data from RUBY-4, our cytopenia basket, which is looking at both ITP, WAH, and cold agglutinin disease, to really inform us moving forward and where we're gonna go beyond lupus and IgA nephropathy. Povetacicept has so many places it can go. We have to be very data-driven and very focused about how we move povetacicept into a number of different indications. We do have interest and emerging interest in exploring povetacicept in neuro indications, and in particular, we're interested in exploring povi and myasthenia sometime in the coming future. So looking at the year ahead, this, as I mentioned at the onset, this is gonna be a catalyst-rich year for the company. You know, we'll be launching a phase 3 study in IgA nephropathy in the second half of this year and our phase 2 study. In the first half of this year, we'll report out longer-term follow-up data from the 80-milligram cohort from the RUBY-3 study in IgA nephropathy, as well as initial data from the 240-milligram cohort. Also, during the course of this year, we'll report out data on primary membranous nephropathy and lupus nephritis, and we expect to get the first data from RUBY-4 in the first half of this year as well. So it will be a catalyst-rich year for the company. We look forward to sharing the updated data from RUBY-3 at a medical conference sometime in the first half of this year. As I mentioned in my prepared comments, more patients are coming through that six-month time point and now starting to reach the nine-month time point, and the data's looking very consistent with what we've seen with the initial presentation. So we won't be able to accomplish this without having a strong financial position. The company's fortunate that it sits on about $365 million in cash, which takes us out into 2026, and that's assuming a very broad development plan and an aggressive investment in our infrastructure going forward. So with that, I'll close, and obviously, we'll open the floor for questions. Thank you for the great presentation, Mitchell. So, maybe I'll kick off the Q&A here with the first question. There are several molecules in the markets that's targeting BAFF and APRIL in development for IgAN. Can you sort of discuss how your platform differentiates from those programs? So as I mentioned earlier, we view povetacicept as being unique and representing best-in-class potential, and that's based on several factors. One is, as I mentioned, we're given in a Q4 week regimen. Two, we're showing the deepest proteinuria reductions at six months. And three, because we're able to inhibit both APRIL and BAFF, we're not just an IgA nephropathy story. Really, povetacicept is a pipeline and a product, and we're interested in taking it to a number of different indications beyond just IgA nephropathy, obviously including lupus, but we'll look at other glomerulonephritis indications, cytopenias, and obviously, we're starting to look at neuro as well. Thank you for that. If anyone in the audience has a question, please raise your hand, and we'll get the mic to you. I can kick off with a second question here. What gives you confidence that you can move directly into a pivotal study in IgAN this year? There's several factors that really accomplish that for us. So one, the strength of the data that we presented at ASN, obviously showing the deepest proteinuria reduction. UPCR reduction is an accepted endpoint for accelerated approval in IgA nephropathy. And there's been strong data to show that the depth of proteinuria reduction correlates directly with clinical outcomes. So, there's precedent there, and in fact, there's other companies that have taken, similar-sized patient, studies and moved it directly into phase III studies in the past year or so. Gotcha. Much appreciated for that. I can ask another question here. What gives you the confidence that the data shared at ASN will not degrade with additional patients and, as we've seen with other programs? Yeah. So, as I made these comments in my prepared comments. So first off, we said historically, when we first presented the ASN data, we talked about the remission rate. We said, you know, because we applied a stringent set of remission criteria, and we saw such a high remission rate, that we had confidence that the data wouldn't degrade over time. So that's now playing out. So we've had a couple more patients, as I mentioned, reach that 6-month time point, and we've had patients out at 9 months as well, and the data continues to look very consistent with what we've seen. So we're not seeing that degradation that's been reported historically with other programs. Yeah. Thank you for that. And, maybe another one from me: Given that you've discussed cash runway to 2026, right, what are some of the key sort of capital allocation priorities for you, in regards to the utilization of your cash runway? Yeah. Our number one and number two priorities are operationalizing our two central trials that we're starting this year. So number one is getting our pivotal trial in IgAN started in the second half of this year. Number two is starting our lupus trial in the second half of this year. But along with that, obviously, we need to build up the CMC profile for the program. So we'll be building up commercial supply for the program as we move forward. So we'll be investing a lot in our manufacturing going forward. Gotcha. I want to emphasize just one other thing about the cash, which is, you know, everyone tends to focus on povetacicept. But I think, as I mentioned in my first comment when we started today, the company has its own discovery platform. The company is founded on a directed evolution platform, and that platform has been highly productive for us. It's put three programs in the clinic. We've delivered a number of molecules to our partners, whether that's the Horizon Amgen collaboration, and we'll continue to use that platform to develop other molecules, and we do have other molecules that we're very enthusiastic about, that we will move into the clinic coming out of that platform downstream. We're not in a position that we want to talk about it today, but that platform continues to be very robust and very productive for the company. Yep. Thank you so much for that. So I think, we're gonna wrap up this session, and just another round of applause for Mitchell for presenting to us today.