Welcome to the Alpine Immune Sciences investor call. Currently, all participants are in a listen-only mode. As a reminder, this event is being recorded. I would now like to introduce Temre Johnson, Senior Director of Investor Relations and Corporate Communications at Alpine. Ms. Johnson, please go ahead. Thank you, Cynthia. Good afternoon, and thank you to everyone for taking the time to join us today. With me on today's call from Alpine are Dr. Mitchell Gold, Executive Chairman and Chief Executive Officer, Dr. Stanford Peng, President and Head of Research and Development, Paul Rickey, Chief Financial Officer, and Dr. Remy Durand, Chief Business Officer. Also participating in today's call are Dr. James Tumlin, professor from Emory University, and Dr. Jonathan Barratt from the University of Leicester. Before I turn the call over to Mitch, I'd like to remind you that we'll be making forward-looking statements during today's call. These forward-looking statements represent our views as of today and are based on our current expectations and consequently involve risks and uncertainties. Actual results could differ materially from those anticipated in such forward-looking statements as a result of such risk and uncertainties. I encourage you to refer to the most recent SEC filings regarding the risk factors associated with these statements. Mitch, please go ahead. Thank you, Temre, and thank you to all those who are participating in the webcast today. I couldn't be more thrilled with the data that was presented today. We have a full agenda for today's call. First, Dr. Jonathan Barratt, one of the preeminent thought leaders in the field, will provide an introduction and overview of IgA nephropathy, the current treatment landscape and the unmet needs, as well as the disease-modifying potential of BAFF and APRIL inhibition in treating IgAN. Dr. Barratt is the IgA nephropathy Rare Disease Group lead for the UK National Registry of Rare Kidney Diseases, and leads the renal research group within the College of Life Sciences at the University of Leicester. Dr. Barratt has also been the principal investigator for international randomized controlled clinical trials in IgAN, and has attended both the FDA and EMEA as an expert witness for new therapies in IgA nephropathy. Stanford Peng, our President and Head of R&D, will then provide an overview of povetacicept and review key data from our non-clinical and phase I activities. I will then ask Dr. James Tumlin, lead author on the poster, to review the initial results from our RUBY-3 study that was presented at the late-breaking session earlier today. Dr. Tumlin is currently a professor of medicine at Emory University and the founder of the NephroNet Clinical Trials Consortium, a nonprofit organization designed to bridge the gap between the pharmaceutical and research industry and community-based clinical investigators. Dr. Tumlin has authored over 100 peer-reviewed manuscripts and is on the editorial review, review boards of multiple journals. We would then like to invite Dr. Barratt back to provide a brief commentary and perspective on the data. I will then, we'll conclude with Stanford, who will discuss our development plans based on the strength of this data set going forward. A late-breaking presentation today at this year's American Society of Nephrology Kidney Week marks one of the most important events for the company since we started Alpine. For the first time, we've shared data in a patient population for povetacicept, our fully owned potent dual antagonist of both the BAFF and APRIL cytokines, that is administered in a convenient, once every four weeks subcutaneous regimen. Patients with IgA nephropathy or IgAN, our low-dose cohort of 80 mg monthly, has demonstrated clinically meaningful improvements in proteinuria, a key readout for IgAN that has been used as the basis for accelerated approval. In addition, as Dr. Tumlin will report, povetacicept may be inducing a rapid remission in IgAN as early as three months, which would be quite compelling for patients. We are also seeing rapid changes in the key disease-related biomarker, Gd-IgA1. We believe these data in total suggest a potentially best-in-class profile for povetacicept in the treatment of patients with IgA nephropathy. Today's results are the first of what we hope to be multiple additional data readouts over the next 12 to 18 months, that will begin to validate the potential broad activity of povetacicept across multiple autoimmune diseases. Based on the strong efficacy and safety data we presented earlier today, and with the support from our clinical advisory board, we now plan to engage with the FDA in order to advance povetacicept in a pivotal study in IgAN in the H2 of 2024, to bring a potentially transformative disease-modifying therapy to patients suffering from IgA nephropathy as rapidly as possible. We look forward to reviewing today's presentation and to sharing additional details regarding our future development plans for povetacicept. In addition to multiple updates on IgAN throughout next year, we also look forward to providing updates on our other indications being studied with povetacicept, including in RUBY-4, our cytopenias trial, for which we are targeting to share initial data in the H1 of 2024. Before we jump into the main presentation today, I'd like to share with you a brief overview of Alpine, for those of you that are new to our story, and give context for how we've advanced Alpine to where we are today. Alpine is a clinical-stage immunotherapy company focused on developing innovative treatments for autoimmune and inflammatory diseases. We founded the company in 2015 with the goal of creating a novel, first, and best-in-class protein therapeutics that could work against multiple targets within the immune synapse. Our rationale is, first and foremost, scientifically driven. All of our molecules have been developed internally using our directed evolution platform. External interest in our platform has also been the foundation of our collaborations with top-tier pharmaceutical companies, including AbbVie and Horizon Therapeutics, which is now part of Amgen. Our wholly owned lead program is povetacicept, which will be the focus of today's call. Povetacicept was discovered in-house, and as you can see from today's data, is a potentially best-in-class dual antagonist of the BAFF and APRIL cytokines, which play key roles in the pathogenesis of multiple autoimmune diseases. What differentiates povetacicept is that using our directed evolution platform, our scientists have engineered this molecule to inhibit both BAFF and APRIL with significantly higher potency than wild type TACI-Fc, with a particular focus on improving APRIL binding. Potency of povetacicept, in addition to its convenient once-a-month subq dosing regimen, combined with today's disclosure, creates what we believe is the potential for povetacicept to have broad applicability across a number of autoimmune indications. Dr. Barratt, I'll now turn the call over to you to give us a review of the evolving IgA nephropathy landscape. So thanks very much. So as you say, I'm Jonathan Barratt from the UK, and what I'm going to do is just talk about the scale of the problem and the impact of IgA nephropathy in populations. I'm going to present some data on a UK study that was published this year. But actually, I just want to draw people's attention to the fact a very similar set of data was presented at the ASN today on a US population, which actually mirrors very closely the UK experience. So what you're seeing me present for a UK population is equally applicable to a US population. So we have RADAR, it's a rare disease registry. We consent patients in the UK to enter the study, and because of our healthcare system, that means every time they have a blood or urine test going forward, that's automatically downloaded into the registry. So we can follow the natural history of IgA nephropathy very closely. What I'm going to do is present some top-line data from that paper. So if we go to the next slide. So what you have here are overall outcomes. If you go to the next. So what I want to draw your attention to on the left-hand side is this, if you are an adult diagnosed with IgA nephropathy in the UK RADAR, UK RADAR data set, at 20 years, almost three-quarters of those adults have developed kidney failure. It's important to note that those adults, when they're diagnosed, are in their thirties. So what we're talking about here are people developing kidney failure in their 30s, 40s, and 50s. So that is no age at all. If you're a child diagnosed with IgA nephropathy, then at 20 years, half of those children have developed kidney failure, and 20 years for a child means they're only in their 30s. So this is a devastating disease. If we now go on to the other side, here, we look at the age at which the patient was diagnosed. So if you look here between the ages of 0 and 18, so if you're diagnosed as a child, and that upward arrow is how old I am, 55. So if you're a child diagnosed with IgA nephropathy, by the time those children reach my age, three-quarters have developed kidney failure. If you're an adult diagnosed between the ages of 18 and 40, 2/3 of those adults have reached kidney failure by the time they reach my age. If you're diagnosed between the ages of 40 and 50, half of those adults have reached kidney failure by the time of my age. This is a devastating disease, and these outcomes reflect what we have available to treat patients at the moment. As I say, this is not a quirk of the UK system. We're not strange people, because this data has been completely replicated in a US cohort, a large US cohort. That data, as I say, was presented at the ASN today. If we go to the next slide. So, if we think about the current treatment landscape, where the opportunities are, and how we might address the pathology of this disease, I just want to take you through what we think is happening. So, the first thing is the presence in the circulation of IgA-containing immune complexes that have the propensity to deposit within the glomeruli, where they can trigger inflammation, scarring, and loss of kidney function. And we believe the main substrate of that immune complex formation is this particular form of IgA. You've already heard it mentioned, Gd-IgA1. It's a particular form of IgA. It's two IgA molecules stuck together, polymeric, and it carries changes to the sugars attached to the IgA one hinge region. So this form of IgA, we believe, is the substrate. It's very sticky. It sticks to itself, it sticks to other serum proteins. It leads to the generation of autoantibodies against the hinge region of the IgA molecule. And we believe the source of this pathogenic IgA is the mucosal immune system. So the immune system that lines our gastrointestinal tract, our genitourinary tract, and our respiratory tract. And of course, all of this occurs on a genetic background, and that genetic background not only determines the risk of developing IgA nephropathy, but then also the risk once you have IgA nephropathy of developing progressive kidney failure. So if we just flick through, that's it. The next one. And so let's think about where these new therapies and the potential therapies fit into how I think we're going to approach management of IgA nephropathy over the next decade. So the first thing is going to be, we need to do basic things well. We need to control blood pressure. We need to deal with those consequences of nephron loss, glomerular hyperfiltration, impact of proteinuria on the tubulointerstitium. This is the same for any form of kidney disease, be it diabetic kidney disease, be it IgA, be it membranous, lupus. It's not specific to IgA. You can see there, we have choices. We have RAS inhibitors, we have SGLT2 inhibitors, we now have endothelin receptor antagonists, and potentially mineralocorticoid receptor antagonists. But of course, none of these agents are gonna target the fundamentals of the immune-mediated kidney damage. We're going to want to be able to switch off the inflammation and the fibrotic signals that are generated when IgA deposits. So what do we have available at the moment? Well, we don't have any anti-fibrotic agents, unfortunately. If you go to the next slide, what we have as an anti-inflammatory is systemic glucocorticoids. We know they are a necessary evil. They're all we've had for many, many years, but they come at a cost. They come at a cost for the patient in terms of tolerability. They come at a cost for metabolic complications, potential cardiovascular complications. So in all branches of nephrology, we are trying to avoid these drugs at all costs. So what else might be available? We might have complement inhibition, would be an alternative anti-inflammatory agent. Lots of complement inhibitors in trials at the moment. But fundamentally, if we want to alter this disease, we need to switch off production of pathogenic IgA. And so how might we achieve that? So if you go to the next slide. So we have the opportunity to deplete B cells, so we could use a CD20 approach. We tried that, it didn't work with rituximab. We have current clinical trials looking at CD38 B cell depletion. We need to wait to see the results of those. And then we have B cell modulators. So we could target the mucosal immune system and try and reduce the production of pathogenic IgA, and we have a drug that's capable of doing that. And in fact, that was the first approved drug for IgA nephropathy. But what I think is really exciting is the possibility of modulating B cell function by targeting the BAFF and APRIL axis. And we have a lot of data, which I don't have time to go into, but we know independent of one another, that overactivity of BAFF can drive an IgA nephropathy-like illness. And indeed, if we make a mouse transgenic for BAFF, it develops IgA nephropathy. We know from genetic studies that genetic risk alleles are associated with the APRIL system and that they can drive IgA nephropathy as well. So what makes perfect sense is to think about how we target this axis to do what we really want to achieve, which is reduce the level of pathogenic IgA. And if we can reduce the level of pathogenic IgA, that reduces the level of immune complexes, it reduces IgA deposition, it reduces those drivers for kidney inflammation and loss of kidney function. And so I think that's what's so exciting about where we are at the moment, is targeting this BAFF/APRIL pathway offers us a real unprecedented opportunity to really get to the very basics of this disease. So I'm going to hand over now to the rest of the team. I think looking at that pathogenic cascade, this is a real opportunity to really target the core of this disease. Thank you, Dr. Barratt. Stanford? Thank you, and good afternoon, everyone. Dr. Barratt has highlighted BAFF and APRIL are two cytokines thought to play key roles in the pathogenesis of IgAN, but also several other autoimmune diseases. In autoantibody-related renal diseases, the differentiation and activation of pathogenic autoreactive B cells is a key underlying process. Such B cells can eventually differentiate into antibody-secreting cells, including plasmablasts and plasma cells, which secrete pathogenic autoantibodies that cause end organ injury. In IgA nephropathy, galactose-deficient IgA1, or Gd-IgA1, forms pathogenic immune complexes with autoantibodies against Gd-IgA1, which can lead to glomerular deposition and renal injury. Analogous pathogenic autoantibodies are thought to play a role in other glomerulonephritis conditions, such as primary membranous nephropathy, where autoantibodies, like those against the phospholipase A2 receptor 1, are thought to be pathologically responsible for kidney damage. Povetacicept is a dual inhibitor of both BAFF and APRIL, designed to prevent the ability of BAFF and APRIL to bind to their receptors. By blocking the activity of BAFF and APRIL, povetacicept is expected to inhibit their effects on multiple immune cells, especially the activation and differentiation of autoreactive B cells, including their development into antibody-secreting cells that are responsible for the production of pathogenic autoantibodies. Structurally, povetacicept is a decoy receptor consisting of a single active domain, as shown in green, derived from the full-length extracellular domain of the TACI receptor, which naturally binds BAFF and APRIL, fused to an Fc. It thus resembles, but is smaller than, other molecules in the clinic, which are based on the whole extracellular domain of wild type TACI, shown in lavender. Povetacicept's TACI domain was engineered by directed evolution to improve its ability to bind to and inhibit BAFF and particularly APRIL. As we recently published earlier this year, povetacicept appears to be quite potent in its ability to inhibit both BAFF and APRIL compared to wild type TACI and other clinically relevant comparators. This table shows IC50s of povetacicept in a cell-based assay used to assess BAFF or APRIL activity. Note that in this assay, the IC50s for APRIL appear particularly improved versus wild type TACI, but in general, povetacicept is at least comparable, if not superior, to monoclonal antibodies against BAFF or APRIL. It's important to recognize that both BAFF and APRIL quite likely contribute to disease pathogenesis. Both cytokines are found elevated in patients with various glomerulonephritis conditions, including IgAN, often in correlation with disease activity. Recently, much attention has been focused on APRIL-specific inhibitors, which have shown promising findings in IgAN. However, it's worth a reminder that BAFF-specific inhibition has been efficacious too. For instance, the BAFF-specific pepti body, belimumab, demonstrated stabilization of UPCR and improvement in eGFR and IgAN, and recently, the anti-BAFF antibody, belimumab, was approved for the treatment of lupus nephritis. In addition, of particular structural relevance to povetacicept, wild type TACI Igs have also shown promising findings in IgAN, as well as at least anecdotally in lupus nephritis and membranous nephropathy. Such observations altogether suggest that both BAFF and APRIL are clinically validated targets, and the combined inhibition of both may result in superior outcomes. Now let's take a look at some of our preclinical data supporting this concept. Here is a preclinical sheep red blood cell challenge model, where povetacicept in green appears to be superior to a wild type TACI comparator in blue, inhibition of APRIL alone with an APRIL antibody in orange, inhibition of BAFF alone with a BAFF-R FC decoy in red, or a combination of the latter two in purple, as assessed by antibody responses on the left and plasma cell counts on the right. Clearly, inhibition of both BAFF and APRIL by povetacicept provided the greatest inhibitory activity in this in vivo study. Such conclusions are further supported by data in preclinical disease models like the NZB/W mouse lupus model. On the left is data published by others, showing that inhibition of both BAFF and APRIL with a mouse TACI FC fusion protein is superior to treatment with a BAFF or APRIL inhibitor alone in terms of kidney disease. In the middle and on the right, povetacicept specifically appears superior to wild type TACI, here represented by telitacicept and CD20 depletion in terms of renal disease, as shown in the middle by histological scores, as well as autoimmune anemia, as shown on the right by hemoglobin levels. Again, inhibition of both BAFF and APRIL by povetacicept provides the most superior outcomes here in terms of autoimmune disease activity. This rationale and supporting data prompted us to regard povetacicept as a particularly compelling development candidate, with the potential to be a highly impactful novel therapeutic in multiple autoimmune diseases. We began povetacicept's clinical development with, and recently reported upon, RUBY-1, a first-in-human, single ascending dose study of povetacicept in healthy adults designed to enable multi-dose patient studies. Here, povetacicept was well-tolerated at doses administered up to 960 mg subcutaneously and intravenously, accompanied by dose-dependent on-target changes in circulating immunoglobulins and some B cell populations, like antibody-secreting cells. The 80 and 240 mg subcutaneous dose levels were chosen to advance the patient studies and scheduled to be administered every four weeks based on the data shown here. 80 mg subQ in green suppressed free APRIL and BAFF for two to three weeks, while 240 mg in gray suppressed both for at least an entire anticipated four-week dosing interval. But the pharmacodynamic effects of both doses, as assessed by circulating IG levels shown in the middle and antibody-secreting cells shown in the lower right, appeared to already be maximally achieved with the 80 mg dose. Importantly, reduction in the IgAN biomarker, Gd-IgA1, was also observed similarly with both dose levels, as shown in the upper right. Therefore, both 80 and 240 mg administered every four weeks were chosen for patient-based studies. Here are four key takeaways regarding the preclinical and translational aspects of povetacicept. One, povetacicept is an engineered dual inhibitor of the BAFF and APRIL cytokines, designed to achieve more potent inhibition of both cytokines than other comparators. Two, povetacicept demonstrates a highly compelling non-clinical profile with superiority in preclinical efficacy models versus wild type TACIs, single cytokine inhibitors, and CD20 depletion. Three, povetacicept has been safe and active in healthy adults, where single doses have been well-tolerated up to 960 mg subQ or IV. And four, povetacicept has a broad development potential with a convenient dose regimen. Patient-based studies are now in progress with 80 and 240 mg subQ every four weeks. Let me now turn the discussion over to Dr. Tumlin, who will review today's poster presentation on RUBY-3. Well, good afternoon. It's my pleasure to review the RUBY-3 data that was presented today at the poster session. The RUBY-3 is an open-label, parallel cohort, dose escalation basket study of multi-dose povetacicept in multiple forms of glomerulonephritis, including IgA nephropathy, primary membranous, and lupus nephritis. Participants are being enrolled in the membranous and lupus nephritis wings. Participants are also being enrolled in disease-specific cohorts, initially at the 80 mg subcutaneous every four weeks, escalating up to a dose of 240 mg after an initial safety review. They are currently planned to receive up to six months of povetacicept, and extendible up to one year, and are assessed for various standard outcomes, including safety, urine protein to creatinine ratio, estimated GFR, and disease-specific biomarkers such as Gd-IgA1 and IgA1. The majority of patients enrolled in the study have been IgA, which has been fully enrolled at the 80 mg dose level and will be the primary focus of today's discussion. These IgA nephropathy participants are required to have had a biopsy-proven disease, within 10 years of study entry, a urine protein to creatinine ratio of at least 0.5 g/g, and an estimated GFR of at least 30 mL/min and be on maximal ACE and ARB therapy. Next slide. As of October 25th, 20 IgA nephropathy patients have been enrolled in the study. At that time, 12 of them were enrolled in the 80 mg dose, which we will refer to as the low dose, and eight to the 240 mg dose. One of the 80 mg participants was withdrawn per investigator decision, and of the remaining nine participants, nine and five have reached 12 and 24 weeks respectively and have UPCR data available. The 240 mg dose is enrolling as well with eight patients, but as shown here, their progress on the study remains early and will be reported at a later date. Next, to give you the baseline characteristics of the trial. In the 80 mg povetacicept IgA cohort appear to be generally consistent with other recent IgA trials, with a mean age of 51 years. A slightly more female cohort and Caucasian demographics. Mean duration of the disease was 4.4 years, with a mean baseline UPCR of 1.3 grams per gram and a mean baseline eGFR of 70. Overall, multiple doses of 80 mg of povetacicept appear to be well tolerated. The majority of adverse events reported have been grade 1 and considered unrelated by the study investigator to the drug. Of note, no injection site reactions, no severe episodes of hypogammaglobulinemia, as defined as an IgG of less than three grams per liter, and no severe infections have thus far been reported. The latter two are, of course, particularly important to note for this class of agents. At this low dose of 80 mg every four weeks, povetacicept markedly improved disease activity in IgA nephropathy, with a reduction in UPCR of 53.5% by week 24. This is a clinically meaningful reduction in proteinuria. Since previous studies have shown that a 30% reduction in UPCR is accepted as a predictive improvement in GFR in this disease. Although we are still early in our experience with povetacicept, even at this low dose, there is already evidence of clinical remission based on UPCR, with reductions in proteinuria in at least one participant below the standard limit of detection by the central laboratory. We examined povetacicept against remission criteria, as shown here. For example, an improvement in UPCR from baseline level of at least 50% to below a value of 0.5 grams per grams, in association with a stable renal function, as assessed by eGFR. By such criteria, which are quite stringent, four out of five or 80% of the participants in week 24 were in remission. This type of metric may be interesting outcome worth following with ongoing and future trials. These findings are highly encouraging and suggesting that povetacicept may in fact be a disease-modifying agent in IgA nephropathy. Importantly, these improvements in proteinuria were taken with a rapid reduction in IgA nephropathy disease-relevant biomarker of galactose-deficient IgA1, which was reduced by approximately 44% within the first month and exceeding 60% by week 12. Of note, renal function, as assessed by eGFR, appears to be stable in this cohort over the first 24 weeks. As expected, total circulating immunoglobulins were also reduced in proportion similar to that observed in the phase I study in healthy adults. Importantly, and as previously mentioned, no events of severe hypogammaglobulinemia, as defined by an IgG level less than three grams per liter, had been noted. Interestingly, but not surprisingly, IgE levels were also reduced, in addition to the reductions in IgG, IgA, and IgM previously described by us and other BAFF and/or APRIL inhibitors. To our knowledge, this is the first report of IgE reductions in humans with this class of therapeutics. IgE has been reported to be elevated in some IgA studies, although its pathologic significance remains uncertain at this time. Either way, these findings might suggest a role for povetacicept in IgA, excuse me, IgE-related disorders. Indeed, povetacicept may have broad potential to benefit multiple antibody-related disorders. In addition to the impact on key IgA nephropathy-related biomarker of gal-deficient IgA1, povetacicept has also been shown significant improvement in key biomarkers in the first and only participant with primary membranous nephropathy enrolled in the study thus far. As a reminder, primary membranous nephropathy is one of the most common causes of nephrotic syndrome in adults without diabetes. It is most commonly associated with autoantibodies against the phospholipase A2 receptor 1 in up to 80% of patients. There are currently no approved therapies, and unfortunately, still about one-third of patients progress to end-stage renal disease over 10 years, and about another third develop chronic kidney disease. Anti-PLA2R1 antibodies are highly correlated with disease activity, and elimination of these antibodies is a key early goal of treatment. Although we know that clinical remission proteinuria may lag for months after achievement of an immunologic remission. In the participant shown here, immunologic remission was achieved at 22 weeks with an anti-PLA2R1 antibody titer below the level of detection of the assay after a baseline level of 209. This may therefore reflect a highly predictive future clinical remission. This degree of biomarker reduction is quite reminiscent of the Gd-IgA1 reduction observed in IgA nephropathy, whereas 80% remission was observed at 24 weeks, shown here again to the left for comparison. So in summary, initial experience with low-dose povetacicept of 80 mg has been well tolerated and demonstrates highly encouraging improvements in UPCR and disease biomarkers in IgA nephropathy, with early evidence suggesting potential for remission. These findings suggest a highly compelling development profile based upon a rapid reduction in key pathologic biomarker of Gd-IgA1, markedly and clinically meaningful reductions in UPCR, and a once-a-month dosing regimen. A higher dose of povetacicept at 240 mg every four weeks is currently being explored and will be of great interest. Further clinical development of povetacicept in glomerulonephritis, particularly IgA nephropathy, is therefore strongly supported. Thank you, Dr. Tumlin, for that excellent summary of the data, as well as your participation in the study. Dr. Barratt, you two have been involved in many development programs in IgA nephropathy in particular. Might you please comment on your perspectives of this data? Yeah, I mean, I echo Jim's comments here. I think this is really exciting data. I think the impact that you've seen with your lower dose of drug is highly impressive. I think the combined reduction in the key pathogenic mediator, Gd-IgA1, that relationship then with a reduction in proteinuria is really powerful, and I think it speaks to the mechanism that you're seeing a parallel change in a key autoantibody in membranous, showing that you're capable of targeting those pathogenic B cells and plasma cells that are driving immune-mediated kidney disease. I think your data is consistent with other drugs in this class targeting this pathway, and I think it reinforces the importance of the BAFF/APRIL pathway in immune-mediated kidney disease and likely beyond and outside the kidney. So I think this is really exciting data. It speaks exactly to what I was talking about earlier, that we can manage this disease at source. We want to turn the tap off. We want to turn the tap off of production of pathogenic IgA, and then everything else will fall into place. But unless we're able to do that safely and effectively, we're going to continually run into problems with our patients, and this drug looks like that gives us a great opportunity to achieve that. So I'm really excited about seeing both the outcome of the higher dose, but also really the potential for this going into a larger study and potentially being available for me to use in my clinical practice. Thank you, Dr. Barratt. Stanford? Yeah, thank you. We're, we're indeed highly encouraged by this data. Here's a look at our now updated development plans for the next year. They include three primary directions. One, advancement to a pivotal trial in IgAN. We intend to approach regulatory agencies as soon as possible about initiating a pivotal trial in IgAN next year. It is possible that the 240 mg dose level may be equally or more attractive to consider than 80, and we will learn more about that over the coming months as we prepare this study. Two, initiation of a proof of concept study in lupus. We remain committed to the development of povetacicept in systemic lupus erythematosus and plan to use the multi-dose experience from the ongoing glomerulonephritis and cytopenia studies to support the initiation of a phase II study next year. And three, continued execution of the open-label RUBY-3 and RUBY-4 basket studies in glomerulonephritis and autoimmune cytopenias, which we anticipate will continue to provide insights regarding povetacicept's potential in other autoimmune diseases. We therefore look forward to a particularly busy and exciting 2024. Let me turn the call now back to Mitch. Thanks, Stanford. Thanks, everyone, for joining today's call. I want to particularly thank our clinical investigators, the study coordinators, and the patients participating in the RUBY-3 study. As you know, you can see from the enrollment has been very strong in the study, and it's because of you that we have the ability to share the encouraging data that we have today. I also want to thank the entire team at Alpine, who has been so passionately working on povetacicept to help improve the lives of patients. This is just the beginning, and we look forward to providing additional updates on povi next year from both the RUBY-3 and RUBY-4 studies. Operator, we'll now open the phone for questions. Thank you, Dr. Gold. If you would like to ask a question, please signal by pressing star one on your telephone keypad. If you are using a speakerphone, please make sure your mute function is turned off to allow the signal to reach our equipment. Again, press star one to ask a question. We'll pause for just a moment to allow everyone the opportunity to signal for questions. Our first question comes from the line of Mike Ulz from Morgan Stanley. Please go ahead. Yep. Hey, guys. Thanks for taking the question and congratulations on the data. I guess just a question for me, just so you think about advancing into the phase III study, seems like you're rapidly moving ahead there. Just curious if you plan to wait for the 24, the 240 mg dose before moving forward there. And then any thoughts around the potential activity at 240 mg? I mean, could that higher dose result in even more promising activity here? Thanks. Thanks, Mike. I'll take the first part of the call, and then I'll ask, maybe Stanford and Dr. Barratt to chime in after that on kind of where they see the 80 mg coming in. So look, this data we think appears to be best in class. A 53.5% reduction in UPCR at six months is highly appealing, and we're going to prepare to launch a pivotal study just based on the 80 mg data that we have in the H2 of next year. Obviously, the 240 mg cohort is still enrolling, so as we're preparing for a pivotal study in IgAN, we'll get data from that, and that will be informative to us, but it's not going to slow us down. We're going to go as rapidly as possible, and this is really based on the feedback from some of our advisors to go as quickly as possible into a pivotal study based on the strength of this data. Dr. Barratt, would you like to comment? Yeah, I would only echo that. I think the data that was presented today by Jim is powerful. I think it is sufficient from my perspective, to justify that dose being used in patients in terms of the efficacy I've seen, both from Gd-IgA1, but also clinical markers of kidney function. I'm going to be very interested in the higher dose, but you can of course be putting going full steam ahead for a plan for your phase III and pivot the dose if the data from the 240 looks significantly different and potentially more efficacious. But I think on the basis of what I've seen, there is no reason why you would not want to be planning your phase III as quickly as possible, because the eighty data, 80 mg data is as good as it needs to be, I think. Yes. Thanks, Dr. Barratt. Gotcha. Maybe just a quick follow-up. Just given the robust results you're seeing here, any read-through to some of the other indications? I know you sort of gave some data for PMN, but you're also looking at a bunch of other indications as well. Is there potential read-through there? Yeah, we think the totality, I'll answer the first part of this, Mike, and then I'll let Stanford answer the second part. We think the totality of the data that we're seeing, both in terms of IgA nephropathy, but the case study that we have in pMN, shows that we can inhibit autoantibody production, which makes us very enthusiastic that we can take povetacicept in a number of different autoantibody-mediated diseases. Which is why we want to see more data come out of both RUBY-3 and RUBY-4 to kind of guide us on what indications we'll go after. Stanford? Yeah, I would, in general, agree. I think to emphasize the data we saw with that membranous participant, the reduction in the pathogenic antibody is far out of proportion than the reduction in total IgG, which suggests that the inhibition of APRIL and BAFF is playing a specific role on that pathogenic B-cell population. So we see that as really optimistic, with the general hypothesis that pathogenic autoantibodies in many diseases are dependent on BAFF and APRIL. But of course, we'll want the data to show that before moving, you know, committing to specific indications. Dr. Barratt? Yeah. What I think is really exciting is that actually we know the pathogenic B-cells for IgA nephropathy are situated within the mucosal immune system, but the pathogenic B-cell plasma cells for membranous are situated in a completely different anatomical location. Mm-hmm. Yet this drug seems to be highly effective in both of those locations, which is something we have not seen with B-cell depleters, such as rituximab. So that really speaks to the fact that this drug is able to impact in different sites of immunological activity, which I think really does open an opportunity to be able to target pathogenic B-cells in different anatomical locations, which I think is critical if you're going to effectively deal with all three of these diseases. Thank you. Thanks, Mike. Got it. Thank you. Congrats again. Thanks very much. Our next question comes from the line of Thomas Smith from Leerink Partners. Please go ahead. Hey, guys. Good afternoon. Thanks for taking our questions, and let me add my congrats on the really stellar data here. Just a question, I guess, first on the dosing regimen. If I could ask the clinicians to comment on the Q4 week dosing and how that stacks up versus some of the other agents in development. How much of a factor do you think the monthly dosing and the convenience might play a role in how they consider using some of these APRIL and BAFF-targeted agents? That's a really good question. This is James Tumlin. So, I have a number of patients enrolled in this trial, and what we find is that the amount of volume that is needed to be injected is of sufficient level that this is not terribly painful for the patients. We have had really no complaints about the frequency or the mode of administration, so it's been actually very well tolerated. And globally in nephrology, there's a lot of movement. For example, belimumab is also being used as a Sub-Q injection. I've had more complaints with that particular agent than I have with the current experience in the RUBY-3 trial. So it's a good thought, but so far it's been very well tolerated. Dr. Barratt, maybe you can comment a little bit on the benefits of a Q4-week regimen compared to a Q2 weeks or Q weekly? Yeah, I mean, I think you're asking the wrong person here. You should be asking the patient. And, you can imagine what the patient will say is, the fewer times they have to stick themselves with a needle, the better. Yeah. I think that is going to. People will really respond to the frequency of administration, but also, as Jim says, the volume, because the volume of. Yeah The drug determines how much it stings. Yeah. I think, you know, we are going to be moving to a position where we are, those things are going to start coming in as a factor. I think that, you know, the least frequent that you have to administer an injection, the better the patients are going to respond to that. But actually, that's something the patients are going to be able to tell you. Thanks, Tom. Any other questions? Got it. Yeah, that's very helpful. And yeah, if I could just sneak in, a follow-up question just, for the management team here. It's great to see the plans for advancement into a phase III study, obviously, in IgAN. I was wondering if you could just comment, given the early findings here, how you're thinking about the potential to start other basket studies in areas like dermatology or neuromuscular diseases? This is Stanford. I'd say we're really interested. We continue to be very interested in those diseases, since there are several that are autoantibody related. You know, I think given the data we've seen with IgAN so far, we certainly want to have that as one of our highest priorities going forward to advance the overall portfolio of povetacicept. But we'll be taking. We'll continue to be taking a look at these other indications as we also get started on moving IgAN forward. Got it. Thanks, Stanford. Super helpful. All right, guys, appreciate it. Of course. Our next question comes from the line of Justin Kim from Oppenheimer and Company. Please go ahead. Hi, afternoon. Thanks for taking the question, and congrats again on the data. You know, we had some time to talk, but maybe for Doctors Barratt and Tumlin, a lot of focus has been directed towards proteinuria lowering as a measure of efficacy, given its use as an endpoint for accelerated approval. Just wondering if you could discuss how important those translations of proteinuria lowering into eGFR protection are, and how the BAFF and/or APRIL's class may be distinguishing them, themselves from other modalities currently in your armamentarium, maybe alluding to some of the presentations expected tomorrow morning? Thanks, Justin. I'll ask Dr. Barratt to start with that, and then Dr. Tumlin, you can chime in if you'd like afterwards. So where we have data for, Nefecon and for Sparsentan, the reduction in proteinuria mapped to the protection in GFR. We know that that relationship is not perfect, and there are confidence intervals around that relationship, but those relationships that we see in those two completed phase III studies, really fit with what we knew already. And I've got no reason to suspect that we wouldn't see a similar relationship if we used the BAFF/APRIL approach. And I think my impression certainly is that this is reassuring to regulators, that the, the leap of faith they took by using proteinuria. Yeah As an accelerated endpoint has borne fruit, because in each of the studies, we're seeing kidney function protection. Actually, when you look at that relationship, it is strong, independent of the mechanism of action of the drug. So, so I have no doubt in my own mind that a reduction in proteinuria that we're seeing with povetacicept, for instance, is going to translate through to protection of GFR decline in exactly the same way as we might see for any other drug capable of generating proteinuria reduction. But of course, the kidney function protection we see is proportional to the magnitude of the proteinuria reduction. So I draw you back to the magnitude of proteinuria reduction that Jim presented, which is substantial, and therefore, I would imagine that will translate through to significant GFR protection. I don't know whether you want to comment, James. Yeah, sure. I totally agree with Jonathan's comments. I think it also extends that this concept that, I mean, proteinuria is actually predictive of outcomes, extends into lupus as well. This is data that's old, that was somehow overlooked and now is being brought back to the surface. Exactly what he was saying, the Sparsentan, as well as the Tarpeyo data, the reduction in proteinuria did correlate into a change, flattening of the GFR slope. It is validating what the FDA agreed to a number of years ago. I think one more thing I would say is that also the data for the RUBY-3 trial also indicates what's typical of B-cell modulation, that you can knock down specific autoantibodies, in this case, galactose-deficient IgA1, and you see in the data there's a lag time of change in program. That's very typical. You see this as well described in the PLA2R antibody data from membranous. So this is all internally consistent. Thank you, Dr. Tumlin. Justin, any questions for you? Yeah, maybe, maybe just as a follow-up. You know, on, on the point of maybe blunting that slope of progression and, and striving for stabilization of the eGFR slope, you know, does that change how you think about patients being managed, that you're not sort of looking at a target proteinuria goal level, but, but that one class might, might appear more attractive because of the ability to maybe achieve that type of, you know, response or, or I guess, you know, clinical remission as, as sort of what's maybe described in, in some of the results, presented this morning? So just to clarify, your question is asking, would one class of drugs, such as povetacicept, a BAFF/APRIL inhibitor, be more appealing because of its ability to impact eGFR? Yes, correct. I honestly don't think you are going to manage this disease with just single approach. I agree. You need to do as I presented, you are going to need to have a three-pronged attack. Fundamental to dealing with IgA nephropathy is switching off pathogenic IgA production, which is what this drug appears to be doing in the data highly effectively. So that's one string. But if you don't deal with glomerular hyperfiltration and you don't deal with the proteinuria response, you are still going to get progressive loss of kidney function. If you don't deal with the inflammation, you are still going to get nephron loss. So we need to accept that we need a combined approach. So don't forget, when we move into phase III, patients will be allowed in on basic standard background therapy. So we're going to manage that, and that's easy. How we deal with the other approaches is more difficult because none of those are approved. I think where we're going to be in 10 years' time, is we will be seeing our patients, making a diagnosis, managing those generic consequences with RAS inhibitors, SGLT2, MRAs, treating any inflammation by blocking the complement system, and simultaneously turning off production of pathogenic IgA, because that's what's going to sort this disease out for patients. We need a three-pronged attack. Thank you. I totally agree with Jonathan's comments. I think that if you don't use his phrase, "Turn the spigot off," you will have an evergoing cycle of proteinuria and renal damage. But having said that, when the damage occurs, products like Ang II, aldosterone, and of course, endothelin, they remain elevated. So this response to injury is a self-propagating progressor of all forms of CKD, IgA included. And so you're going to have to have multi-pronged therapies, including ACEI or ARBs. My opinion also is that MRAs will be important, and I think the ERAs are going to be a very important addition to this. But again, if you just go with that one particular pathway and you don't turn off the galactose-deficient IgA1 production, I don't think you'll have an effective long-term outcomes. Thank you, Dr. Tumlin. Thank you, Justin. Okay, great. Thank you. Our next question come from the, excuse me, comes from the line of Gregory Renza, from RBC Capital Markets. Please go ahead. Great, good evening, Mitch and team. Congrats on the data, and thanks for taking my questions and also for holding this great event. Mitch, maybe a question for Dr. Barratt and Dr. Tumlin, and just kind of building on the prior comments and as Dr. Barratt earlier certainly commented and mentioned the consistency of the data with the class IV and the reinforcement of the BAFF/ APRIL approach. And maybe just building on, you know, where you see the sequencing and even the combination potential of povetacicept fitting into the development landscape and knowing that we've discussed the differentiation. Just want to think about building out on that, those comments a little further. Thanks so much. Just to clarify, Greg, just to make sure I got the question, Where do you see povetacicept as an APRIL/BAFF inhibitor fitting in, in the sequencing of treatment for these patients, correct? That's correct. Okay. Dr. Barratt? I don't think there's going to be sequencing at all. I think sequencing is the completely wrong approach. I'd just like to give you the scenario, we see patients when they present, and we get to intervene, most of those have already lost half their nephrons- Right. Because their kidney function is already impaired. So they are essentially running on a single kidney at 30 years of age, with 50 years left of life. That means that we need to preserve that kidney so that they can avoid dialysis. That's what the registry data shows from the UK That's what the data shows from the US And actually, there was another poster from Canada that showed almost identical data. So we need to be far more proactive. And so for me, it will be making a diagnosis, giving the patient the diagnosis following the kidney biopsy, simultaneously starting a B-cell-directed therapy like povetacicept, giving the patient an anti-inflammatory drug if their kidney biopsy shows inflammation, and starting those core treatments that deal with the generic consequences of kidney damage. We have to start these drugs immediately if we are going to stop kidney failure in the lifetime of our 30-year-olds because they're coming to us, having already lost half their functioning nephrons. We haven't got time to wait and sequentially add drugs and delay intervention. I agree. So, the nephrology community globally is moving away, which has been sort of the way we've handled CKD for so long, is sequential therapies. In fact, if you actually disrupt pathway X and pathway Y, you have a combinatorial approach that improves the outcomes. I think that, the other aspect that has not been talked about much is that another branch tree, in my opinion, is going to be looking at the original biopsy and determining how much complement activation is going on. So when you have these IgG anti-Gd-IgA1 autoantibodies that are part of the mechanism by which complement is activated, that will add another layer upon which you will add, probably complement therapy, depending on the individuals. What we don't have, and Johnson and I have talked about this a number of times, is a vetted level of galactose-deficient IgA1 that would help clinicians decide when to either turn on or turn off B-cell therapy. This is in the membranous world, we track PLA2R antibody titers, and when they begin to rise, we oftentimes institute therapy based on that, even before proteinuria develops. Thank you, Dr. Tumlin. Greg, one more question for you, or is that it? Yeah, just one more, just maybe on the development path and the velocity of enrollment and trial progress. And Mitch, as you've mentioned, nice enthusiasm, nice momentum as well. I'm just curious what you and the team identify as some of the pushes and pulls in order to maintain that momentum. Thanks so much, and congrats again. Yeah, I think, you know, the enrollment in the study, the RUBY-3 basket trial was strong, particularly in IgAN, and I think it's because, as Dr. Barratt mentioned, there's a lot of investigator awareness of this pathway. They're very familiar with the APRIL and BAFF space. They're comfortable giving these drugs, and so enrollment was very swift. We're going to try to replicate that in our other trials like we did before, and obviously, you know, we have a lot of experience in the lupus landscape. But I think there's deep interest in using these agents, these agents in this patient population, which is why enrollment's been so strong. That's really helpful. Thanks again. Thanks again. As a reminder, if you would like to ask a question at this time, please press star one. We'll pause for just a moment. There are no further questions. This brings us to the end of the time for questions. Dr. Gold, I'll turn the call back over to you. Thank you. I'd like to thank everyone that participated in today's call. Thank you, Dr. Barratt. Thank you, Dr. Tumlin, for taking the time out of your busy schedule here at ASN. It's very much appreciated. Thank you, everyone, listening to our extended call today. Have a great evening. This concludes today's conference call. You may now disconnect.