So good morning and good afternoon, everyone. Thanks for joining us today at Oppenheimer's second day of its annual healthcare conference. I'm Justin Kim, one of the senior research analysts at the firm, and it's my pleasure to welcome Dr Mitchell Gold, Co-Chairman and CEO of the company, as well as Dr Remy Durand, CBO, for this fireside chat on Alpine Immune Sciences. So thanks for joining us today. Thanks, Justin, for having us. Maybe just to start, could you just give us a brief overview of sort of the company's focus in severe and inflammatory and autoimmune disease, as well as what's sort of been the latest on the company? Yeah. Well, I think to do that, you have to take a little bit of a step back and look at kind of where the company came from. So the company was formed in 2015, and our goal was to use our directed evolution protein engineering platform to create multi-specific proteins that could hit two different protein structures simultaneously. So that platform has been highly productive. We've actually put three molecules into the clinic off of that platform, and then we have a collaboration with Horizon, now part of Amgen, where we deliver a number of molecules to them off of that platform. Povetacicept now is the, yeah, obviously the key focus for the company. Povetacicept was specifically engineered to overcome some of the liabilities that our team was very familiar with, and specifically to overcome some of the lack of APRIL binding that's associated with the wild-type TACI proteins. In addition, the wild-type TACI proteins currently in development are given on a weekly dosing regimen, and povetacicept was engineered to be more potent than that. So not only does it bind APRIL much more potently than the wild-type TACIs, but it was also engineered specifically from the start to be able to be given in a monthly dosing regimen. As a result of that, because we invented that program in-house, it wasn't in-licensed, we have composition of matter intellectual property on povetacicept out to 2041 with the ability to extend it beyond that. So that's beyond what you would get specifically from biologics exclusivity. We can go into a number of different indications off of povetacicept and move forward from that. We don't owe any third-party milestones. We don't owe any third-party royalties. Because we only give 80 mg of protein a month as opposed to anywhere from 400 to 12, you know, 1.2 grams of protein, our cost of goods should be lower than others currently in development. All right. Great, great. And maybe just to sort of talk about povetacicept and sort of its initial debut at ASN, can you just sort of talk about maybe, you know, what we know about povetacicept today and as it pertains to the sort of the treatment of IgAN and sort of what the promise and sort of the follow-through, you know, the team is hoping to deliver on even maybe with IgAN and also beyond it? You know, the whole concept of modulating B cells for autoantibody-mediated diseases, specifically B cell modulation in IgA nephropathy patients, has now come to, you know, the forefront. So I think historically we used to look at how the BAFF/APRIL inhibitors would potentially fit in with other paradigms. And now, given where the field is going and, the promising data that we're seeing from others in development, I think you're going to see B cell modulators being used as frontline treatment. IgA nephropathy is probably a much bigger indication than I think any of us anticipated. All of us are enrolling our trials very rapidly. In fact, our 240 mg cohort, in our RUBY-3 study has now far exceeded the enrollment that we had in the 80 mg cohort. And I think that's an indication for the number of patients that are out there. B cell modulators will play a, you know, really important role. We think that a once-a-month dosing regimen with the ability to hit APRIL and BAFF very potently and best-in-class proteinuria reductions will be very appealing for physicians and patients. Great, great. Remy, do you want to add on top of that at all? Yeah, I think just even stepping back as a reminder to everyone here, you know, BAFF and APRIL are two key critical cytokines for B cell development. And blocking them is, is critical to stopping the pathogenesis of autoimmune disease for, for IgAN, but also many other indications. BAFF and APRIL also play roles through their receptors, on other cell types as well. So by blocking these two critical cytokines, we, we what we've demonstrated so far is best-in-class proteinuria reduction in IgAN, but the development opportunity is much broader than IgAN alone. And we view this as, as really a pipeline and a single product opportunity. I agree with Mitch that IgAN is a much larger indication than I think many initially anticipated, and I think BAFF/ APRIL inhibition will, will it's so exciting because it has this potential to be disease-modifying. We've seen that already, through the stabilization of eGFR, very clear reductions of proteinuria, and deep reductions in Gd-IgA1 in IgAN. But, you know, just to add on to that, Justin, you know, one of the reasons we can push into these other diseases is because of the product profile that I shared with you. A once-a-month dosing regimen, with long composition matter IP and a favorable cost of goods. We can think about other indications like lupus. I know, you know, we've shared with folks that we have other indications that are interested beyond that, either coming out of our RUBY-3 trial like pMN or some of our cytopenia basket data coming out later on this year. And we continue to generate additional preclinical data in-house that suggests a role of povetacicept in a number of different autoimmune diseases. And in fact, some of this preclinical data is, you know, significantly compelling that even though it's preclinical, it's been accepted for oral presentations at some of the upcoming meetings that we'll share that data with. So povi is going to have a role beyond IgAN. We'll be valued, I think, initially on what we do in the IgAN space. But our goal is to really turn povi into a pipeline and a product. Understood, understood. You know, just sort of zeroing in on the 80 mg data that the team had presented at the ASN meeting and sort of that really profound proteinuria reduction achieved at the 80 mg dose. Can you just sort of talk about maybe any updates since that point? I know at the beginning of the year you sort of talked about how additional patients were sort of be consistent with what we had seen already. And then just like as we move to the 240 mg dose, like what are we trying to actually see or find or accomplish with that dose? I'm getting an echo, Remy. You getting that too? A little bit? Is this me? No. Well, I'll go ahead. Well, I'm happy to answer that question. So, you know, our confidence has only increased, you know, since I shared that initially, you know, early on in the year that we're not seeing a degradation in proteinuria reduction. In fact, we now have several patients that are out at nine months, which is obviously the endpoint that we look at for accelerated approval. We, when we look at those patients that are out in nine months, we're not seeing a degradation at that, at that time point. In fact, if anything, we're seeing a deepening. So, you know, we continue to have confidence that potent APRIL and BAFF inhibition in a once-a-month dosing regimen with best-in-class proteinuria reductions will be highly appealing for patients with IgA nephropathy. Got it. In terms of the 240 mg data, as I said, you know, that cohort has enrolled extremely well. In fact, it's, you know, far exceeded what we enrolled at the 80 mg cohort. We're not expecting to see, at least in IgA nephropathy, any clinical differences between the 240 mg cohort and the 80. We'll continue to track it. It's still early days with the 240 mg cohort, but we'll continue to track that throughout the year. In our lupus trial, I remind you that we'll study both the 80 and 240 mg dose levels. But we're anticipating that in our IgAN pivotal phase III trial, unless we see something dramatically different come out of the 240 dose level, that 80 mg given once a month will be our pivotal dose that w e take forward in the phase III trials. Okay. Got it, got it. You know, you, you maybe hinted at this. I don't want to sort of go too deep into that, but you know, that, that sort of there is a little bit of a debate between six and nine months, you know, in terms of what type of proteinuria reduction, you know, should we be seeing out of agents? Is there going to be divergence between how this class operates? Do you think that sort of maintained proteinuria is kind of the goal here, or, you know, how should we be thinking about whether, you know, these levels should be decreasing further, you know, nine months being kind of that accelerated approval endpoint for, for proteinuria lowering? Yeah. I think that's a really good question. What I would point you to is the Pitcher and Barrett paper when they look at an analysis from the RaDaR Registry. When you look at that paper, I don't know if you've looked at that paper yet or not, but when you look at the Pitcher and Barrett paper from the RaDaR Registry, what they show is that the deeper your proteinuria reduction is, the better your survival outcomes are and the better your outcomes are for inhibiting patients going on to end-stage renal disease. So in fact, for every 10% reduction you have in proteinuria, there's roughly a hazard ratio of a 10% improvement in progressing to end-stage renal disease and death. That starts at six months and it goes all the way out to 24 months. Now, obviously, the nine-month data is the key endpoint that you want to see because it's the endpoint that the FDA uses for accelerated approval. We don't expect that to change. eGFR is the endpoint that we use for full approval, but I think at least with B cell modulators, what we're seeing is that the correlation between proteinuria reduction and eGFR stabilization continues to be very strong. Mm-hmm, mm-hmm. Got it, got it. You know, maybe going to sort of, you know, your discussions around the 80 mg dose really shaping up to be a potentially pivotal dose. You know, what are the moving parts towards getting a study initiated? We've seen some sort of similar trajectory where, you know, you, based on that trajectory, could be in phase III development in the second half of this year. So just kind of curious, what the team needs to accomplish, whether it's regulatory interactions or manufacturing, etc., to sort of really get that study up and running. We're in a really good position in that regard. So, and just to kind of correct, it's a phase III trial, not a phase II trial. So it'll be a pivotal phase III trial that we've guided that we would start in the second half of this year. You know, we're preparing for that both from an operational perspective. Internally, obviously, we have ongoing regulatory discussions. But, you know, we've guided investors that we anticipate starting that trial in the second half of this year. We also anticipate that we'll be about a year to a year and a half behind the other B cell modulators that are going to launch in the IgA nephropathy space or the anti-APOs that are currently in development. but we'll be entering the market with the best-in-class product profile, once-a-month dosing, dual inhibitor, both APRIL and BAFF, best-in-class proteinuria reductions, and a favorable cost of goods profile with no milestones or royalties owed to any third parties. We think that'll be very appealing in the IgA nephropathy space. But our goal is to move beyond that. So it's not just IgA nephropathy for us this year. Our other main objective, which is a big one for us, is to start our pivotal phase II study, our lupus study that we're going to call Denali. And that study will be a very important study for us because it'll validate the role of povetacicept in a major indication such as lupus. And we're going to be very aggressive about enrolling our Denali study. Remy, I don't know if you want to add on top of that at all. Yeah, I think in addition to that, in addition to the phase II lupus study, which will start in the second half of the year, we'll also have a continual cadence of readouts or regular cadence of readouts. The goal for us is to establish proof of mechanism or proof of concept in many indications. Again, IgAN is the first year. We also showed a case study in PMN. So we'll have updates for IgAN in the first half of the year. We are targeting to have updates this year in other indications in RUBY-3, so PMN as well as lupus nephritis potentially. Then within the autoimmune cytopenia basket, also guiding towards an update primarily in ITP for the first half of the year. So again, you know, that, that trend will continue in the second half of the year as we start those two studies, but also into 2025 as we evaluate additional indications, as well. We've, we've also shown preclinical translational data in myasthenia gravis where we demonstrated numerical superiority versus efgartigimod in CD20. So again, it's, it's laying the pathway for, potential expansion into multiple indications as we go forward. Understood. Maybe just sort of going back to the discussion around proteinuria and eGFR lowering, the APRIL and BAFF axes seems to be a very profound way to drug this disease, where maybe that there is that relationship, right, between proteinuria and eGFR, but it seems like with this class, it might even be more profound that you might get even more sort of benefits, right, which is what we had seen with atacicept. And so I'm just kind of curious, whether you're looking ahead, right, to sort of those, those sort of perspectives and that, you know, proteinuria lowering is important, but, you know, driving that as much as possible, you know, the narrative is maybe even shifting to, well, you know, we just want to stop the disease, right? We want kidney function to be preserved and whether that's sort of, you know, what the team is setting its sights on, in the long run. Well, I would, I think proteinuria is going to continue to be important because, while you're measuring eGFR and as patients are coming in for their monthly visits, they're most concerned about what their proteinuria is doing. I kind of analogous to biomarkers that you'd use in oncology, right? So even though you may be living longer, you're going to want to be able to track the diseases over time. And proteinuria is currently our best, you know, relevant biomarker that we have for IgA nephropathy. And it correlates directly with eGFR outcomes. And as I mentioned earlier in the RaDaR Registry, we saw that the depth of proteinuria reductions actually correlates with your progression to end-stage renal disease. So a deeper proteinuria reduction, particularly early on, gives you benefits in how you progress to end-stage renal disease. I think the fact that you're seeing B cell modulators have such a profound effect is because they're hitting the right cell types and they're able to drop the autoantibodies against galactose-deficient IgA1. So you're preventing the immune complexes from forming and then you're preserving renal function downstream. So right now, you know, I think what you're seeing as a class is that B cell modulators have the ability to preserve renal function. I think that's become the bar. Like you have to see a stable eGFR with these molecules. And we're continuing to see that. And that's going to be highly appealing for patients. They get on these drugs early and they stay on them because you have preservation of eGFR downstream. Okay. Yeah, I would add too, there's an important concept of remission in IgAN that's starting to emerge. Remission typically in, I think, most investigators in KOLs' minds, in addition to eGFR, encompasses proteinuria. And the concept, the goal for treatment is to drive proteinuria as low as possible. You know, no amount of proteinuria is really should be tolerable. And that's a different mindset for the community where 1.5-1 grams was typically tolerated as a baseline. Now there's a real push, an important push to get patients as low as possible, below 0.5 grams, below 0.3 grams even. And that's where, you know, again, this proteinuria in addition to eGFR stabilization is going to be important as we move forward and as these drugs start to become commercialized. That I have to add on to that. In that, you remember at ASN, we presented a pretty stringent set of remission criteria where you had to have a 50% reduction in your UPCR from baseline and you had to have stable eGFR and your proteinuria had to be less than 0.5 grams per gram. So that concept of remission is now coming into vogue. And however you set it, you know, we've set a stringent set of criteria. Remy mentioned 0.5. It could be 0.3, but it's clearly low, right? That's, I think, where the field is going. And so where, I think, you saw the more hemodynamic drugs that are focusing on hemodynamic parameters, these true disease modifying agents, like B cell modulators, are going to be used very early on in the disease because of the benefits they're going to have for patients. Got it, got it. You know, along that vein of sort of this idea of remission criteria and, you know, I guess, you know, if we can look at some early biomarker sort of proteinuria approval endpoints in lupus nephritis, for example, as being well accepted by regulatory agencies and there's been a lot of flexibility just using proteinuria at nine months for accelerated approval. You know, do you see that landscape shifting even further, that, you know, to your point about having these remission criteria that's actually achievable with this class of agents, that that could be something that povetacicept is a beneficiary of, you know, sort of once, you know, maybe we see that confirmation in some of the other ones that might be a year or year and a half ahead, that you could sort of have a glide path, based on sort of how you think about the development of povetacicept? We're not anticipating that. We're anticipating that, you know, proteinuria will still be an endpoint that's used for accelerated approval and that full approval will require eGFR. And keep in mind, you know, we'll, we would have already started our phase III trial, you know, by the time the other trials are reading out. So, you know, we're anticipating that it will be proteinuria for accelerated approval and eGFR for full approval. If you look at our data, we have best-in-class proteinuria reduction. So, you know, we're confident that that's going to continue to be the parameters that the FDA uses. If that changes, that's great for patients, but we're not operating the company in that respect that there's going to be a change in the regulatory paradigms around that. Okay, got it. And one of the other things that we've been sort of getting asked on is just in terms of the dosing between 80 mg and 240 mg. I know you sort of set the stage in terms of what we can expect or what's reasonable in IgAN. But you know, we've heard, right, competitors talk about maybe increasing the dose on one of their regimens and sort of prolonging the interval of treatment. You know, is that something that the team has looked at for povetacicept? I mean, you're tripling the dose, right, with a 240 mg dose. And so just curious, any thoughts there or whether you've sort of? Well, keep in mind that it's 80 mg given once a month. So we're not tripling the dose, right? Because, so if you look at povi, yeah, we, we are for other indications beyond IgAN, you know, there's a potential to think about a, you know, Q3 month dosing regimen with povi potentially at 240 mg or some alternative dose. But even at 80 mg in our commercial formulation, you know, we're covering APRIL and BAFF and we're, we're our injectate volume is 0.5 ml or less, right? So it's the lowest injectate volume that'll be given in an autoinjector in a commercial formulation. And we don't feel a big need at this point to go into a Q3 month formulation. We have very strong data with a monthly formulation currently and we don't, we don't feel like a Q3 month formulation in IgAN would be a big shift, you know, for patients. So, you know, we like where we sit from a commercial perspective right now. But maybe for other indications where, you know, could be, you know, indications that we're not prepared to talk about now, but where a Q3 month or even a Q6 month formulation could be interesting. But not for IgAN. Okay. Remy, I don't know if you want to add on top of that. No, I think that's right. We're actively working on, you know, different scenarios and different modeling. I think, you know, 240 mg or higher dose once every three months could be feasible in the future for other indications. Right now we're focused on 80 mg once a month. I think it's also worth noting just the enthusiasm we've, that this regimen has been received by the community, in terms of enrollment, having a once-a-month low-dose regimen at 80 mg has been, you know, very well received and has helped tremendously in enrollment too. Understood, understood. And with respect to the sort of class of therapies targeting this, you know, another thing that's been sort of, discussed is just kind of the safety profile in IgAN, right? IgAN being a relatively, asymptomatic disease for many patients and so wanting to have like high tolerability and high safety. Can you guys comment on povetacicept as it relates to, you know, what you're seeing so far on, on the front of, hypogam and, and maybe, you know, what sort of the communication plan or strategy is around sort of discussing maybe ADA profiles or what we should be looking at in terms of, you know, whether there's a consistent continual benefit with the drug? You know, I think that's just it. Really, when you stop just for a second and pause and look at all the enthusiasm around B cell modulation, it really shows how far we've come. I think Remy probably remembers when we first started this program, one of the key questions all of us used to get, I think, in this space was around the historical safety signals associated with B cell modulation. None of us are seeing that now. So whether you're looking at the pure anti-APRILs, the wild-type TACIs, or engineered TACI fusions like povetacicept, all of us in general are seeing that the drugs are incredibly well tolerated. I think that's because we conduct our trials in a much different way now. And we're able to monitor patients and follow them much more closely than was done, you know, 10+ years ago when atacicept was early on in development. So, to answer your question specifically, you know, we're not seeing any clinically significant ADAs. We have a very low rate of ADAs. It's probably because of mechanism of action of the drug in some ways. Too, you know, the drug is incredibly well tolerated. I think that's one of the appealing aspects of it. And again, that's something that's not specific to povi. I would say that's, you know, more of a class effect because we monitor patients so well in our clinical trials. Okay, great. You know, just on that point, I mean, is proteinuria lowering and Gd-IgA1 sort of, are those like the right markers to look at long-term in terms of, you know, like it's not clinically significant. All patients are sort of achieving, you know, those effectively clinically meaningful results, right, with. Well, I, I'll go back to my comments earlier, which is depth of proteinuria reduction matters. So if you go back and look at the RaDaR Registry and the Pitcher and Barratt paper, specifically in that paper, they point out that starting at six months and going to 24 months for every 10% reduction you have in proteinuria, it directly affects your progression to end-stage renal disease and survival. So depth of proteinuria reduction does matter. I think beyond that, you have to see stabilization of eGFR. I think that's the bar that we're all kind of setting for ourselves right now. I don't see Gd-IgA1 as being a good surrogate for that. We look at Gd-IgA1 as kind of being relatively weak. It's not a clinical predictor of disease outcomes like proteinuria is. Okay, understood. Yeah, I just kind of meant that the curve at the very trough, right, stays a trough, right? That doesn't bounce around is sort of an indicator that there are no meaningful ADAs and things of that nature impacting, you know, the response you get over time. Yeah, I mean, I think we all kind of throw out on Gd-IgA1, run around the same level around 60%+, right? So. Okay, got it. Got it. Yeah. Because that's why I don't think it's the best biomarker for predicting where patients are going to end up from a clinical perspective. Mm-hmm. Mm-hmm. Maybe shifting gears to the, the work sort of in, in broader glomerulonephritis. You know, the initial data with PMN, I think, kind of like had the spotlight stolen from IgAN in, in many ways. But you know, just wondering if you know, how we should be thinking about those early results, like what we can expect in the future. And just kind of like the landscape there relative to IgAN and sort of povetacicept's role. Well, I mean, look, it's a, it's a huge unmet medical need. You know, it's probably equal number of patients with PMN as you see with lupus nephritis. There's very few drugs in development there. And the one patient that we presented at ASN had an immunologic condition. I can tell you that in RUBY-3, we've enrolled a couple more patients with PMN and we'll be continuing to track what povetacicept does there. And as we mentioned in our previous comments, that's something that, we'll present, we'll be presenting, you know, throughout the course of the year. Okay. And in terms of like the landscape, is it right to think about povetacicept as entering a field where maybe depletors are really like the only option for patients today? Yeah, yeah, largely that's true. I mean, there is nothing approved in PMN. Many patients are treated with rituximab, of course, as a, as a CD20 depletor. But importantly, CD20 is expressed on a fairly limited set of B cells and it does not get expressed highly or at all on later stage plasma cells and plasma blasts. With BAFF/ APRIL inhibition, the benefit is a broad spectrum of cytokine blockade that takes away the survival factors and stops the progression, not only of B cell maturation and differentiation, but then also at the far end of the spectrum, production of pathogenic autoantibodies, which is, you know, why we see this really potent selective blockade of pathogenic IgG against the autoantigen PLA2R1. You know, and then again, there are other benefits of targeting the cytokines beyond that are separate from targeting depletors, you know, safety, et cetera. You know, depletors, you have to look at them that, you know, they're more of like a shotgun type of approach. Right? As Remy mentioned, they don't cover the broad spectrum of B cells. And I think what we're seeing with povi is that, you know, we're hitting a very specific, we're hitting a broad section of B cells. But we're also preserving long-lived plasma cells. So you're not seeing that your protective IgGs are really dropping significantly. We're not seeing hypogam. But if we look at the PMN patient that you mentioned, you are seeing significant drops of pathogenic autoantibodies because those are the short-lived plasma cells that are highly dependent on APRIL and BAFF as trophic factors for their growth and survival. So there's something about APRIL and BAFF and how specific they are to pathogenic B cell clones that is really important for not only IgA nephropathy, but we think for other autoantibody immunities as well. And when we look at this preclinically, what gets us excited is when we look at other diseases beyond IgAN, whether that's lupus or other diseases that we haven't presented yet. You know, we're very excited about how broad povi can go into development plan. In fact, in our RUBY-3 trial, we just expanded that, to include ANCA vasculitis patients as well. So, you know, we'll continue to look at povi across a number of indications. IgAN's a massive commercial opportunity for the company in near term, but our goal is to build a really broad immunology franchise based on povi's broad development potential. Okay. I'm looking forward to that. Maybe just a last question as we're sort of running out of time, but you know, talking about that sort of what's on the cusp. You know, Myasthenia gravis has, you know, the team has presented some, you know, I think model data, preclinical data there. And it's definitely been a really exciting area of interest for investors we speak with. You know, just wondering how you think about the timeline there and where we might you know, see initial PoC data or see a study initiated. Like, do you have any sort of you know, broad, rough guidance in terms of like, is that sort of the next indication as you sort of allude to the stuff that's sort of in the works? Like, is that one sort of the frontrunner there or just any color guidance on that front? You know, we obviously the commercial opportunity for myasthenia is, you know, obviously large. We've seen that with other drugs in development there. It's also a very private space. But when you compare povi to the current drugs in development there, we compare very favorably preclinically. So it is of deep interest to us. With that being said, our goal this year is to make sure, you know, we're in the red zone for punching IgAN into the end zone. We're going to launch our lupus trial, which is really important for us. And I think once we feel comfortable that those are launched and on their way, then we can start thinking about other indications like MG. As I mentioned, you'll see us present other preclinical data and other very large and significant indications that we think povi could have a role in that may be less crowded than MG. So we'll need to do that analysis internally to see what makes the most sense for us, for us as a from an NPV perspective. Okay. Just a final maybe point on next near-term catalyst. The updates for IgAN, WCN and ERA-EDTA are sort of top of mind. So could you maybe talk a little bit about what we can hope to expect at those medical meetings? Are those the right places where we might expect to see updates for povetacicept? Those are beautiful conferences. One's in Buenos Aires, one's in Stockholm. Really nice places. We like those places. We've guided that we'll be presenting data, updated data on the 80 mg cohort, so long-term follow-up from 80 and initial 240 mg cohort in the first half of this year. Those would be, you know, nice conferences for us to share data at. Okay, great. Well, we'll look forward to it. Thanks again for joining us and looking forward to all the updates. Thanks. Appreciate it, Justin. Thank you, Justin. Thanks, everyone.