All right. Good morning, everyone. Thanks for joining us here on day three of the Leerink Partners Global Healthcare Conference. My name's Tom Smith. I'm one of the Senior Biotech Analysts here at Leerink, and it's my pleasure to welcome our next company to the stage, Jade Biosciences, and really happy to be joined this morning by CEO Tom Frohlich and CSO and Head of R&D Andrew King. Gentlemen, thanks for joining us. Really dynamic time in the space. We saw the Vertex data earlier this week. Obviously a lot to talk about, but maybe Tom, you could just kick us off with a little bit of background on the company, all the progress you made over the course of the last 12 months, and then what you're looking forward to most. You have some data coming right around the corner, but things that you're looking forward to in 2026. Yeah, absolutely. Thanks, Tom, and the whole Leerink team for hosting us. It's very much appreciated. Yeah, it's been a really exciting dynamic time in IgAN, but also for Jade as a company too. We're actually only fairly recently formed, actually. Andrew started the company in around June of 2024, but we think we made extraordinary progress during that time. We're set up to really be the best-in-class company in a number of different autoimmune diseases. We are taking that best-in-class approach, and we've managed to make so much quick progress because we've actually have access to three assets from a company called Paragon. Our approach really is to go after biologically validated targets in big therapeutic areas, and really use this protein engineering approach to have really high-affinity binders to the targets that we're going after, and also use the Paragon expertise in half-life extension. Really that half-life extension and high-affinity binding really does have two really big benefits. One is you get more complete inhibition of the target, so really trying to maximize the biological activity of that target, and you can do that for an extended dosing period. Really to reduce patient burden in terms of fewer number of injections, which drives convenience, which should also drive a lot of uptake in all of these therapy areas. We're really excited. We have the three assets. Our lead program is an anti-APRIL initially targeting IgA nephropathy, an area that I'm sure we'll talk a lot about through the fireside chat. We think it's a really big opportunity. We think the anti-APRIL class is gonna move to frontline therapy because it's disease-modifying, has the possibility of stabilizing eGFR. We believe we have a straight shot for a best-in-class therapeutic within the anti-APRIL class, and we can talk about how we plan to differentiate there as well. That program is currently in a phase I trial looking for a readout in the next quarter. A very exciting time for us. Our first set of clinical data as a company, and then we're looking to use that to springboard very rapidly into patient trials. We have another program, JADE201, which is just getting to the clinic in the second quarter of this year. That's a BAFF-R. It's a B-cell depleting mechanism with applicability across a number of different autoimmune diseases. We'll look to have a readout for that program in 2027. We have a third undisclosed program, which we'll talk more about as we get closer to the clinic, but follows that same playbook where we're looking for that best-in-class activity in a biologically validated area. All underpinned by a very strong team. Andrew and I both came from Chinook Therapeutics, and also a strong financial position. We closed last year with $336 million, which takes us through multiple milestones into the first half of 2028. Awesome. Thanks for the background. Yeah, let's start on 101. You described just maybe high level level set us. You in-licensed this from Paragon. What exactly were they optimizing for? I think when people think of the Paragon antibodies, they think of obviously the half-life extension, so trying to optimize for less frequent dosing, but also perhaps lower immunogenicity. What other aspects were we trying to optimize for with 101? Yeah. Well, Andrew, you played a big role here, so you wanna take that question? Yeah. Really three elements relative to the first-generation agents. One was improved potency relative to the relatively modest potency of those first agents, which is somewhat limiting in their ability to deliver the full efficacy available to the MOA. We were also interested in optimizing patient convenience. IgAN's diagnosed in 20- to 30-year-olds, so as young adults needing disease-modifying therapy lifelong, potentially for decades. We do believe that convenience and reduced patient burden is gonna be a significant value creator for IgAN patients. That was the incorporation of the YTE half-life extension to really deliver the full disease-modifying efficacy of the MOA with the most convenient infrequent sub-Q dosing profile. The final element you highlighted has become more in focus recently with the sibeprenlimab approval and the label identifying a fairly extensive ADA profile. 34% of participants were ADA positive, which resulted in a 40% decrease in plasma exposure, and a reduced impact on proteinuria, the primary endpoint of that clinical trial. JADE 101 is designed as the first fully human anti-APRIL monoclonal antibody, so a decreased risk of immunogenicity relative to the first-generation humanized agents. We also selected JADE 101 with a novel epitope that avoids large immune complex formation that can occur with sibeprenlimab binding the trimeric APRIL protein through this daisy chaining-like effect. We feel like the fully human nature and the avoidance of large immune complexes with JADE 101 reduces the immunogenicity risk. That's great. Optimizing for the affinity. We have femtomolar affinity here. How do you expect that to translate clinically? Is it deeper proteinuria reductions, more rapid reductions, better outcomes longer term? Like, how do we think that's gonna manifest? Yeah. JADE101 is femtomolar in its binding affinity to APRIL, about 50 femtomolar. That's 750-fold higher than sibeprenlimab, 2,000-fold higher than zigakibart, and this will allow rapid APRIL neutralization and complete APRIL neutralization sustained through very low plasma concentrations of the drug given its high binding affinity. We do plan to incorporate a loading dose strategy into the ultimate IgAN dosing regimen, which, as you highlight, will result in very rapid complete APRIL neutralization to get deep IgA reductions, and fully efficacious exposures from the beginning dose with the goal of driving IgA and proteinuria down as far and as fast as possible relative to the other agents. Potency obviously overcomes some of those hurdles of the first-generation agents not being able to fully capture the full efficacy available to the MOA at the doses they've taken forward. Maybe just to expand on that, sibeprenlimab, that's the Otsuka medication that was just approved at the end of 2025, they actually did their phase II with an IV body weight adjusted dosing, where they had three different dose levels, and they did see quite a clear dose response in terms of APRIL suppression, but then also in terms of proteinuria reductions, absolute changes from baseline. Then very importantly, they saw double the number of patients at the highest dose get into clinical remission, which is defined as below 0.3 g a day or less, so double the amount getting into remission at the high dose than the middle dose. As Andrew mentioned, they're not as potent as JADE101, and the dose that they brought into phase III and they're commercializing is a sub-Q formulation that's roughly equivalent to that middle dose, and they just can't fully capture that efficacy with a sub-Q formulation that's convenient for patients. With the femtomolar potency and the half-life extension, we aim with JADE101 to be able to capture that full efficacy and replicate that high dose IV sibeprenlimab. Got it. Room to improve potentially on efficacy. When we think about the half-life extension, maybe just describe it, what we've seen pre-clinically, and what we're aiming for in terms of dosing interval. Do you wanna take that one? Yeah. What we're seeing preclinically is a 27-day non-human primate half-life that's more than threefold longer than sibeprenlimab, so effectively half-life extended. One of the challenges for the first generation agents in the clinic has been this really pronounced impact of target-mediated drug disposition on the profiles, which limits the pharmacodynamically active runway of those agents, so making it a little bit of a challenging translation into the clinic. For that reason, we haven't guided on our estimates of human half-life because they'll be nuanced, being dose-dependent, the hallmark of the presence of TMDD. But generally, you see a two- to four-fold increase in half-life going from non-human primates to the clinic with YTE half-life extended antibodies. We feel like with that preclinical profile, we can guide to deliver at least a Q8-week maintenance dosing interval. That would be six injections per year, less than half as many as sibeprenlimab and povetacicept at once a month. Based on our market research, we do really see a big inflection point from going from Q4 to Q8 in terms of patient and prescriber preference to significantly reduce the burden. You do get incrementally greater uptake in these market surveys with extended intervals beyond that. We do really think that a Q8-week dosing interval that provides the full disease-modifying efficacy to the MOA has the potential to create significant value for IgAN patients. That makes sense. When we think about the other side of the efficacy-safety equation and potential to differentiate on safety, debate among investors between targeting BAFF and APRIL together versus APRIL mono, I think there's potentially some real advantages to just APRIL alone. How do you guys see the potential to differentiate on safety tolerability? Yeah. We do believe that selective APRIL inhibition can provide the full disease-modifying impact of B-cell modulation in the most targeted and selective way, without unnecessary immunosuppression, that's introduced from BAFF. IgAN is a plasma cell-mediated disease, and that's an APRIL-responsive, not BAFF-responsive cell type. What we're seeing consistently through the phase II programs of selective anti-APRILs versus anti-APRIL BAFF dual inhibitors is very similar efficacy profile, similar impact on mechanistic biomarkers like IgA and pathogenic Gd-IgA1, similar reductions in proteinuria, hematuria resolution, and most importantly, eGFR stabilization. A really remarkable disease-modifying impact without any clinical evidence that adding BAFF inhibition on top of APRIL provides better clinical responses. We've seen that play out now across three separate phase III clinical trials, with the selective anti-APRIL sibeprenlimab reporting a 51% placebo-adjusted proteinuria reduction at nine months versus 42% for atacicept and 49.8% for povetacicept, the dual APRIL BAFF inhibitors. In these, more robust pivotal registrational trials, we're yet to see BAFF provide additional clinical benefit. But what we do know from selective BAFF inhibition in other indications where Benlysta is approved in lupus, you do get a slow B-cell depletion over time through starvation of this important pro-survival factor. And this B-cell depletion isn't accompanied by additional clinical benefit. We feel like there's really strong rationale in these young patients requiring lifelong therapy to provide the most targeted, the least broadly immunosuppressive impact. In the absence of additional clinical benefit from BAFF inhibition, we feel that represents a potential long-term liability that's just unnecessary in these IgAN patients. Yeah. Let's double-click on the competitive landscape and talk a little bit about the most recent data set we saw earlier this week from Vertex, their interim RAINIER readout. As we look at those data, it looks like proteinuria reduction kinda lands in the ballpark of the other agents that we've seen. A little bit of regression from their prior experience. Safety, maybe a little bit TBD. I don't think they disclosed or mentioned some important details, hypogammaglobulinemia rates, et cetera. How do you guys view that data set, and I guess how validating do you think that is for perhaps the APRIL mono approach? We've had long-held conviction since our days at Chinook that APRIL is really driving the clinical activity in IgAN specifically. In other indications where there is more of a B-cell component, then definitely BAFF is playing a role. But in IgAN specifically, we think that APRIL is the driver. Now as Andrew mentioned, we've seen these two datasets really confirming that you are not getting additional clinical activity through BAFF. It really reinforces to us that selective immunomodulation through APRIL is really the driving force. We know that IgAN is actually emerging as quite a big area. I think a lot of people had pegged the branded market in the U.S. at around a $10 billion opportunity. What we are seeing now is with the expanded label that Otsuka received with sibeprenlimab where there's no proteinuria restriction, it really had an indication statement saying any patient at risk for progression with IgA nephropathy is indicated for treatment with the selective anti-APRIL class, that anybody above 0.5 g a day is eligible for these medications, and they will move to frontline therapy. Then you couple that with the fact they priced at the highest end of the range that people were anticipating. They priced at a $30,000 price per vial, which is $390,000 a year. You know, you factor in there's 170,000 IgAN patients in the U.S. Roughly 2/3 of those are treatment eligible as defined by the guidelines above 0.5 g a day. You very quickly get to a market that's well beyond that $10 billion mark. We're now estimating it's probably $20 billion or greater. There's some other analysts that say it's even a little bit higher. We believe the anti-APRIL class is gonna dominate that segment. It is getting more competitive, but we do believe with the JADE 101 profile, having that opportunity for capturing the full efficacy available to the mechanism, that extended dosing interval, which for these patients who are diagnosed in their 20s and 30s, convenience is really gonna matter. Having half the number of injections with capturing that full efficacy, we think is really well positioned to capture a big portion of that market. Yep. Some very strong promising early trends as we look to really build out this market. It seems like certainly a trend, a little bit of an urgency from clinicians to start to use more advanced therapies earlier in the treatment paradigm. The guidelines are certainly helpful in that respect. I wanna turn and talk a little bit about your upcoming phase I data and maybe just help frame expectations, obviously with this mechanism expecting APRIL levels to be pretty much obliterated. What are you targeting in terms of IgA levels? Yeah. It's gonna be a very meaningful clinical readout for us because in healthy volunteers, you can measure APRIL reductions, you can measure decreases in IgA, which translate with the other agents in this class have translated perfectly into what you anticipate seeing in patients. We think this dataset is very, very de-risking for us, and then also will help us fully characterize the medication to enable us to move forward really, really quickly. Do you wanna talk a little bit about what we expect with biomarkers? It is a really biomarker-rich phase I study. We will report the safety, tolerability, and PK that you typically get out of a healthy volunteer study. Also ADA rates, which will become increasingly in focus, because of sibeprenlimab's label. The really rich dataset that sets up for a de-risking of the program is the biomarker responses because they are so translatable and predictable of clinical benefit ultimately in IgAN patients. What we hope to see is this rapid, deep, and sustained APRIL suppression, that's accompanied by the biological max reduction in IgA that's sustained for at least eight weeks to be able to set up that eight-week dosing interval. What we've seen with the first generation anti-APRILs is, in healthy volunteers, they administered high IV doses they weren't ultimately able to take forward in development, but helped define the biological max response to full APRIL suppression in healthy volunteers. Those agents reported about a 55% max IgA reduction following a single ascending dose in healthy volunteers. If we can match that 55% reduction with it being sustained for at least eight weeks, we'll consider that a big win for JADE 101 to be able to move forward with that full disease-modifying efficacy with a Q8-week dosing interval. Got it. Maybe talk about potential next steps post phase I readout. Obviously, the team quite a bit of experience from the sibeprenlimab development program, but how quickly could you move this into an IgAN phase II? Yeah. We've actually provided some guidance that we're conducting startup activities for a phase II just at risk before we disclose the phase I data. We have guided that phase II we will initiate it around the middle of this year with data in 2027. In that trial, because of the full characterization we'll get from the phase I study, we don't need to do extensive dose ranging. We'll feel pretty confident with the dose and dose interval and be able to move very quickly. We're targeting a small trial, probably about 30 patients, open label, where we can generate some data. We were also looking to see, you know, how quickly can we move into later stage trials, because we do realize with this mechanism, it's biologically de-risked. The technology is fairly low risk. We think our biggest risk is around commercial risk, and we wanna try to close that gap to the agents that are further ahead. We wanna move as quickly as we can. The current base case is doing something like Alpine with povetacicept, where they initiated a phase III just based off of six patients worth of data in their phase II. We're also looking to see are there ways to shortcut that and move even a little bit faster. Is there anything, I guess that you, I mean, this is already a setting where one pivotal study seems sufficient for approval, but you do have FDA like adamantly arguing, "We wanna get advanced therapies in the hands of patients more quickly." Like, any opportunity from a regulatory feedback perspective you see to potentially streamline and maybe narrow that gap? Yeah. We really are encouraged by the potential evolution on that front. Historically, registrational trials have been a single pivotal study with proteinuria at nine months, the primary endpoint for accelerated approval, and then confirmatory endpoint eGFR at two years for full approval. That's worked well with the first round of agents. With the evolving landscape, number of new therapies approved in IgAN patients, the potential to do two-year placebo-controlled trials becomes increasingly challenging and potentially unethical to watch eGFR decline over that two-year period in placebo patients. The FDA has recognized this and has requested the National Kidney Foundation to hold a workshop in April with regulators, global KOLs, sponsors, including Jade, and the patient voice to discuss strategies to support continued innovation in IgAN with the recognition that we need to move on from the original trial design. We think that sets up really well for the anti-APRIL mechanism of action because you are seeing these large disease-modifying treatment effects both on proteinuria, but most importantly on eGFR stabilization relative to this really predictable 5-6 ml/min eGFR decline per year in placebo patients. Potentially shorter placebo-controlled trials using earlier time points for eGFR to support full approval could provide a really efficient way to move JADE 101 into registration trials and towards full approval. That's great. Yeah. It's really remarkable. Almost prototypical disease for this, like, streamlined clinical regulatory pathway. There are other anti-APRIL compounds that are in development. Some of them also going to have extended half-life. I guess in your market research, like you've already highlighted potential to potentially improve on efficacy, less frequent dosing, potential safety advantage over the dual inhibitors. I guess when we think about moving 101 into a frontline setting, what does the market research suggest is gonna be the kinda predominant driver of the decision-making on the clinician end? Like is it the less frequent dosing or the efficacy? Yeah. It's a great question, and we did do a small market research with a targeted number of nephrologists where we did ask the question, looking at varied efficacy results and varied dose intervals and looking at different profiles. We do see that physicians, like any therapy area, they're primarily driven by efficacy, and they wanna see at least as good efficacy as the other agents out there. Then, of course, on the safety front, that's a big driver too. What we did see really toggling market share quite a bit was that dose interval. This does really feel like it's a market where convenience is gonna matter. As we talked about, these patients are diagnosed young. They have very few other comorbidities. They're actually asymptomatic, so they don't wanna be thinking about their disease on a continual basis. Having that prolonged dose interval is actually gonna be a big driver of choice for clinicians and for patients. We did see that in one study that we did, we just held efficacy constant just to see what role that convenience was playing. We did see that when you go from four to eight weeks, that's where you start really getting a big inflection point to capture a lot of share. At that level, we were capturing roughly 50% of the share with an eight-week versus a four-week dose. Caveat there is it's, you know, not adjusted for launch timing and some other factors, but we do see that's the big area. If you do get beyond 12 weeks, you do get incrementally more share, but it looks like the big driver and inflection is from that four to that eight-week spot. That makes sense. How do we think about potential applications for anti-APRIL beyond IgAN, and I guess how are you guys thinking about indication expansion potential? It's definitely like with a drug like this that does seem to have a very good level of safety, very convenient for patients. We definitely wanna explore it beyond IgAN. We do think IgAN's a huge opportunity. As you likely know, Tom, you get these big drops in IgA. You get similar drops in IgM and relatively sparing of IgG. With that profile, we think there are other indications that we can go after, particularly a number of IgM-mediated diseases, things like multifocal motor neuropathy, anti-MAG neuropathy, where you could potentially have this similar disease-modifying approach. We think like MMN, multifocal motor neuropathy, is an interesting area. We know some of the complement inhibitors are being studied there, but we think this is an area where you could take away that driving pathogenic driver of disease, and potentially have a big role there. That is something that we'll look into, potentially running like a basket trial in those areas. We think with the pricing that Otsuka set, that could potentially be a very attractive market. Those are things that are on our radar. We also are keeping a very close eye on sibeprenlimab with Otsuka. They initiated last year a phase II study in Sjögren's, which could potentially be a massive opportunity. We are intrigued by the biology and wanna have a close look at it, but we're pretty happy that Otsuka's running the study to have that proof of concept. It should read out in the middle of 2027, and we'll keep a close eye on that and see if that's something we wanna explore as well. Yeah, that makes sense. I wanna shift gears and talk about 201, and I guess similar sort of question, we in-licensed this also from Paragon. What exactly were we optimizing for? How does this compare to ianalumab? Yeah. JADE201 is a half-life extended afucosylated anti-BAFF-R receptor monoclonal antibody following in the footsteps of ianalumab from Novartis. It's a next generation B-cell depleting strategy, which has broad therapeutic potential across a whole variety of different autoimmune diseases. Ianalumab is currently in six different phase IIIs across a variety of autoimmune indications. Ianalumab has great pharmacological properties in terms of its ability to potently bind the BAFF receptor, drive enhanced effector function mediated ADCC, and block BAFF receptor signaling. This dual mechanism of action that not only provides deep circulating B-cell depletion, but the potential for enhanced B-cell depletion within the tissues right at the source of autoreactivity, and tissue injury. The one limitation we identified with ianalumab is it has a relatively short human half-life of only 10 days. Our goal with the design of JADE201 was to retain those attractive pharmacological properties of ianalumab, but incorporate half-life extension with the LS mutation, with the goal to provide a more durable extended receptor occupancy with the potential to deliver the full efficacy available to the mechanism of action, while again providing a convenient infrequent sub-Q dosing profile. That's great, and it's been really encouraging, I think, to see the breadth of the ianalumab development program. It expands so much here over the last 12 months. This also provides a potential opportunity to get very quick proof of concept data in patients. I I think you've teed up RA as an initial setting. Yeah, talk about how you're thinking about the phase I and maybe help frame expectations for that. Yeah. With an enhanced B-cell depleter, it's not possible to go into healthy volunteers for that first in human study. We have selected rheumatoid arthritis as the most feasible population to do that. You can really think of the RA first in human study as a surrogate for healthy volunteers. It'll allow us to get a detailed characterization of safety, tolerability, PK. It's also a very biomarker rich first in human study, directly measuring BAFF receptor occupancy and following the depth and duration of B-cell depletion. RA patients do respond rapidly to B-cell depletion over a short period of time. Opportunistically, we have included exploratory endpoints of joint pain, swelling, and CRP to calculate a DAS28 score to get some early potential signals for efficacy. It's unlikely that RA will be a strategically prioritized indication for future development, but this data set will set up a detailed understanding of the PK/PD to advance into prioritized indications following the first in human study. That makes sense, and we're gonna see so much data over the next 12-24 months. It's really probably gonna help guide those strategic decisions. All right. Unfortunately, we're up against time, but thank you Jade team for joining us, Tom and Andrew, and some exciting data right around the corner. We'll stay tuned. Great. Thank you. Thanks so much, Tom. Thanks, Tom.