There we go. All right. Good morning, everyone. Welcome again to TD Cowen's 46th Annual Healthcare Conference. Tyler Van Buren here, Senior Biotech Analyst at TD Cowen. For our next session, I'm very pleased to have a hybrid presentation and fireside chat style Q&A with Arcus Biosciences. It's my pleasure to introduce Andrew King, the Chief Scientific Officer of Jade Biosciences, as well as Robert Goeltz, the Chief Financial Officer. It's a privilege to have you both here with me. I'll go ahead and hand it over to you to get it started. Hi, good morning, everyone, thanks, Tyler, and thanks to Cowen for having us. We're Jade Biosciences. We're a autoimmune disease-focused biotech company, spun out of Paragon Therapeutics with license to 3 assets. Our lead is an anti-APRIL, currently focused on IgA nephropathy with interim phase 1 data slated for the first half of this year. Our second program is an afucosylated anti-BAFF-R. That's JADE201, following the footsteps of Novartis' Inebilizumab. We slated that we'll have that in the clinic in the second quarter of this year in RA patients with interim data in 2027. Our third program, for which we just announced that we had nominated the lead candidate for, the target is undisclosed, but we will disclose that target, and that's about a year behind JADE201, so expected to be in the clinic in the first half of 2027. Kicking things off with JADE101. IgAN is a very large market. We think that the $10 billion here is actually understated based on what we've seen in for two reasons. One, the new KDIGO guidelines, the very loose label for Sibeprylimab, which basically allows for any patient with IgAN to be treated. There's no proteinuria threshold. And then, of course, the pricing for Sibeprylimab, which was recently approved. We believe that the anti-APRIL mechanism is poised to be the frontline treatment for IgAN. It's a plasma cell-mediated disease. APRIL is the cytokine that you wanna target. We have designed JADE101 to have best-in-class attributes in terms of binding affinity to maximize efficacy, to deal with a selective anti-APRIL MOA. We've added a YTE mutation for half-life extension, so to give it the best-in-class convenience profile. We'll have biomarker-rich data, as I mentioned, in the first half of this year, we think that this MOA is very well characterized, we can have a pretty efficient path to market. As I mentioned, again, it's a very large market opportunity. Higher proteinuria is associated with greater risk of kidney failure. We've seen in the epi, these are patients bucketed on the left. You can see the lower the proteinuria, the longer you have until EGFR or kidney failure. Of course, the higher the proteinuria, you see the exact opposite. The goal, and this is in the new KDIGO guidelines, which I'll touch on in a moment, is to really get proteinuria as low as possible, and we believe that maximal APRIL suppression is the way to do that. We've also seen on the right side, it's a relatively large rare disease, but it's a relatively large rare disease with between 150,000 and 200,000 patients in the U.S. 60%-75% are gonna be over that 0.5 grams per day requiring therapy per the treatment guidelines. Ex-U.S., it's obviously a very large market too, especially in Asia. New KDIGO guidelines are twofold. These are very encouraging to the anti-APRIL class. The first generation of therapies had decent proteinuria reductions. You were not seeing EGFR stabilization because they were not treating the upstream cause. This anti-APRIL class that we're seeing new clinical data on and we've now seen an approval on is really treating the disease upstream. We believe that with these new KDIGO guidelines, coupled with the clinical activity that we're seeing in this MO, think of the bird for most IgAN patients. JADE101 designed with three key features, potentially best-in-class efficacy. Again, that deep potency, you really wanna crush APRIL as much as you possibly can. Do it with six or fewer injections per year, so that would be half of what we've seen with the most recently approved anti-APRIL and the ones that are in clinical development, late-stage clinical development, I should say. Avoid this unnecessary immune suppression by not targeting BAFF. Again, target the APRIL cytokine. We've seen broad B-cell depletion is ineffective in IgAN in clinical trials, due to it being a plasma mediated disease, and so APRIL is again, the cytokine that you wanna target. We've seen some of this readout in the phase III trials. There were 2 phase IIIs that have read out so far. One is coming up soon. In the selective anti-APRIL, that was Sibeprylimab from Otsuka, we saw a 51% placebo-adjusted proteinuria reduction versus atacicept, which was a 42% placebo-adjusted proteinuria reduction, Sibeprylimab being the selective anti-APRIL, atacicept being the dual APRIL BAFF. Why do we believe that there's still efficacy on the table? We get this question a lot, as you might imagine. If you take a look at the Sibeprylimab phase II, which is the most robust of the phase II trials run so far, there were 40 patients per cohort. They tested three IV body weight adjusted doses, 2 mgs per kg, 4 mgs per kg, and then 8. They saw the highest levels of absolute proteinuria reduction of 63% at that top dose. Importantly, and this is very important as we think about the recently adopted KDIGO guidelines, we have these really ambitious treatment goals to get proteinuria as low as possible. 26% of patients went into clinical remission, so it's below 0.3 grams per day, which is basically an effective cure versus only 12%. That's over a twofold increase. We think that clinical remission rates will be a secondary endpoint to watch out for, in addition to, of course, absolute proteinuria and then EGFR stabilization. We think that nephrologists are a relatively conservative bunch, so they wanna prescribe the most effective and the safest therapy. JADE101 has, I think a lot of the attributes that I already characterized. It was a de novo antibody discovering campaign with a novel epitope, we have composition of matter into the mid-2040s. In NHPs, we exhibited a 3x half-life compared to sibeprylimab in NHP, so a 27-day NHP half-life, you can see the accompanying deep and prolonged IgA reductions that we saw in NHPs preclinically. Our phase I trial was initiated in August of last year. Single study of 4 sub Q doses, placebo end of my six to two per, the endpoint or safety. We think that IgAN in part-particular and unique to the disease is very bio-rich. We've seen a very nice translation from all the way from NHPs and into patients, ultimately the clinical endpoints such as proteinuria and EGFR with these key biomarkers. The key pharmacodynamic biomarkers that we'll be looking at are APRIL, IgA. We'll be also looking at, IGX, IgM, IgG. We'll also be looking at, in addition to safety, we'll be looking at immunogenicity. I think a common question that we get is on the ADA profile of sibeprylimab. We'll obviously be tracking ADAs early, and we think that we'll be able to have enough to see, you know, to know if we have a signal there or not. We'll be reporting on that as well. We've seen this nice translation in sibeprylimab, zigakibart and povetacicept. This is basically showing they're circled in yellow, is their go forward doses where you do see APRIL suppression, you know, Sometimes down to 100%. However, you don't see it very durable. One of the things that we wanna do is basically show this maximal APRIL suppression, coincident maximal IgA reductions to the biological max, But show it for a longer period of time to really characterize our dosing strategy going forward. We think that leveraging a lot of these data, in addition to our own, will enable us to develop a very well-characterized model to project our dosing strategy going forward, not just for phase II, but also for phase III development. We see a very nice correlation between a healthy volunteer IgA reduction, then ultimately the IgA reductions that you see in patients is basically 1 for 1. Similarly, you see that IgA reductions going forward into uPCR reductions, which is of course the primary endpoint for accelerated approval. Setting up the competitive landscape, you have sibeprylimab, atacicept, povotecicept and zigakibart. Two of those are selective anti-APRILs in sibeprylimab and zigakibart. Of course, atacicept and povotecicept being the dual APRIL BAFFs. What we have preclinically shown is the highest binding affinity. It's over 750-fold more potent than sibeprylimab, around 2,000-fold more potent than zigakibart, and yet 20-fold more potent than an already very potent povotecicept. If you look at the bottom, we think that convenience is going to be a very key differentiator for these patients. In addition to having the best in class efficacy, you wanna do it in a, we believe that you wanna do it in a targeted, select anti-APRIL MOA, but you wanna do it with the fewest injections per year. Our target is 6 injections or fewer for these patients, which we believe will be commercially differentiated. That's JADE101. JADE201 is our second program. This is a afucosylated anti-BAFFR. What we're really trying to solve for is B-cell depletion. While it's been proven to be very effective in autoimmune diseases, you get deep reductions, you get... What ends up happening is you get this compensatory mechanism where you get this B-cell rebound with the current generation of B-cell targeting therapies. These cells will ultimately repopulate and then mitigate the potential efficacy available to the MOA. When Paragon was designing this molecule, they saw some of the early and encouraging results from Ianalimab, which this is another afucosylated anti-BAFFR, and that kind of showed this proof of concept for overcoming some of these barriers, including, and importantly, these clinical, these clinical tissue B-cell depletions, which you typically find as a limitation with the current crop of B-cell reducing therapies. We have this dual MOA of direct cytotoxic toxicity via enhanced effector function. That's, again, that's the sort of the first-gen where you get this enhanced, you know, very rapid B-cell depletion. The second MOA, as you can see on the right part of the slide, is showing that you get this enhanced B-cell depletion by BAFF starvation to avoid this repopulation, which is again, a compensatory mechanism to the existing B-cell therapies. JADE201 was really designed for a few reasons. It was designed to basically retain the desirable features of Ianalimab. We have novel CDRs with composition of matter patents into the mid 2040s, and we have an LS mutation in the FC for JADE201 to enable a potentially longer half-life. That has really two purposes. One is to have the best, you know, convenient dosing regimen for patients, but also you can have a longer, target coverage and potentially better efficacy as well. We've shown preclinically that we've retained the desirable attributes of Ianalimab with BAFFR binding and BAFFR blockade, ADCC activity, et cetera. We've shown good PD markers as well. Nice dose linear PK, BAFF receptor occupancy, as well as B-cell depletion. We've solved for in non-human primates, the one key limitation to Novartis' Ianalimab. It has a relatively short human half-life of approximately 10 days, and we've shown in NHPs that we have approximately doubled that. Potentially for longer, target coverage to have better efficacy, but also to have the a longer dosing interval. JADE201 is slated to begin a phase 1 study in the second quarter of this year. It'll be in RA patients. You can think of RA as kind of our de facto healthy volunteer study because it's an enhanced B-cell depleting agent. Ethically, you don't wanna go into healthy volunteers. There'll be 36 RA patients randomized 5- 1 between treatment and placebo arms with data in 2027. We'll be looking at safety and tolerability, of course, and some of these key PD markers, BAFF receptor occupancy, B-cell depletion, et cetera. We can also look at some of these exploratory efficacy markers, though we don't believe that RA will be a priority indication. We haven't eliminated that per se, but you do get nice, you know, nice relatively rapid activity in RA patients. We'll be monitoring these exploratory efficacy endpoints and then making decisions around our go-forward excuse me, strategy in terms of indication selection. It's a very big market, basically go anywhere where tocilizumab can go. Obviously, we're not planning to go in all of these indications, but we do get very excited about the potential for many of these indications. Our expertise in-house currently is in the rheumatology and nephrology spaces. There are some first-in-class indications. First in class meaning where Ianalimab is not being studied. Novartis is in, I think, 6 phase III trials across multiple different indications. A couple of them have read out, including in ITP and Sjögren's. There are several more slated to read out over the next 12 months. We do have our eye, as I mentioned, on some of these first-in-class indications as well. It's a very large and exciting opportunity. Just to recap, we have JADE101 with data in the first half of this year, healthy volunteer biomarker-rich data to enable our dosing strategy for late-stage development. J201 will be in the clinic in the second quarter of this year with data in 2027. I should also mention we'll have our phase II data for JADE101 in 2027 as well. That'll start in the middle of this year. JADE301, we will disclose the target in the second half of this year. That's about a year behind JADE201. We ended 2025 with approximately $336 million of cash and runway into the first half of 2028. I think it was exactly 15 minutes. That was very impressive. Thanks for that, Brad. Maybe you can join us over here. And Andrew is joining us as well for the Q&A portion. The phase I data coming by the end of the first half, it's not your average phase I data set, right? In terms of the data that we're gonna see, even though it's in healthies, should be very translatable to patients, allow us to directly compare 101 to the other programs out there. And if you guys put up what I think you're gonna put up, Jade's at an incredibly attractive valuation right now. We could start with that phase I data. I guess, will it be all 32 patients, I believe it was? Can you just talk about, even though we don't know the doses, talk about the dose range that you're exploring. The disclosure in the first half of this year will be a robust characterization of all the cohorts. As you mentioned, the healthy volunteer PK/PD biomarker responses have been highly consistent from healthy volunteers to IgAN patients and ultimately predictive of clinical efficacy, given the strong association between APRIL and IgA reduction and proteinuria benefit and eGFR stabilization for the first-generation agents. We haven't disclosed the doses, but we have highlighted across the four cohorts, it includes pharmacologically active but not fully therapeutic maintenance doses, and that maintenance dose is designed to be a 2 mil injection, no more frequently than every 8 weeks. Loading dose strategies, it's really important with half-life extended antibodies, particularly with mechanisms impacted by TMDD, to saturate that with a loading dose up front and drive fully efficacious exposures from the beginning, and then some safety coverage across the four dose levels. Great. Since you talked about TMDD, maybe you could just elaborate on that for folks who are less familiar and how that might affect exposures, and then also, what you expect the human half-life and dosing interval to be for 101. Yeah. TMDD or target-mediated drug disposition has been really influential on the first-generation anti-APRIL monoclonal antibodies, with both zigakibart and sibeprylimab limited clinically due to this rapid nonlinear clearance that happens as a result of binding the APRIL target. For JADE101, we designed it with a novel epitope with a attempt to avoid large immune complexes that can happen when monoclonal antibodies bind trimeric proteins like APRIL, and lead to rapid, nonlinear clearance. By design, we're attempting to mitigate, TMDD, but because it has been so impactful, it makes it more challenging to translationally predict the non-human primate PK profile into humans. It's relatively easy to predict linear clearance, slow linear clearance of YTE half-life extended antibodies, but TMDD is a challenging phenomenon, to translationally predict. For that reason, we believe we'll have a half-life that can support a Q8-week dosing interval. Although PK is important, our main focus is on the biomarker-rich response which will tell us exactly how much APRIL suppression, how long it's achieved for, and the accompanying IgA reduction. It's really the biomarker responses, and the population-based pharmacodynamic modeling that we'll present that will define the dose and the dose interval which we can move forward at. Great. You guys showed that awesome figure up there that I love with the phase three doses and the IgA and APRIL suppression, and it's, you know, for a novel agent, I feel like crushing APRIL down to 0% is kind of table stakes, and we'll see how long you guys are able to do that for. I guess, the next progression from APRIL is IgA, right? What reduction in IgA would you want to see, and how do you think about the bar for durability there as well? Yeah. Yes, I think with these, with these agents, you typically see a maximal single-dose IgA reduction in the 55% range. What we would wanna show is that biological max activity but showing it extended out for a longer period of time to enable that Q 8-week dose. Great. Just your confidence in that, you know, IgA reduction translating to proteinuria reduction, and what do you think is the maximum possible proteinuria reduction in these patients? Yeah. We think the sibeprylimab phase II study has defined that biological max response. In that study, the high dose, they used 8 milligrams per kilogram IV, body weight adjusted dosing, a dose that they weren't able to take forward in phase III when they shifted to a flat subQ dose. That dose essentially reduced APRIL to 0 in all patients for the 52-week treatment period. It really defines the biological max response to full APRIL depletion. They reported a 63% reduction in proteinuria from baseline, along with EGFR stabilization at 12 months. We feel that really defines what's maximally achievable by an anti-APRIL in this high-risk IgA patient population typically studied in phase III. Great. As you mentioned, Brad, there's like a one-to-one in terms of the correlation of IgA reduction from healthies to IgA patients. The R values are about as high as you typically see. Maybe we'll move to safety. Just, you know, what are you guys focusing on with respect to safety? You mentioned immunogenicity. What do you wanna see there? Also B-cell depletion and hypogammaglobulinemia. Yeah. How big of a focus is that for you guys and for KOLs? Yeah. I think again, I think the sibeprenlimab study was the most robust to show maximal APRIL suppression, right? That was a 52-week period where APRIL was basically zero in all 40 patients. It was an unremarkable safety profile between the various doses. However, one thing that we've now seen in the sibe label is approximately 30% of patients had ADAs, which resulted in a 40% reduction in exposure. We think that the APRIL characteristics of full APRIL suppression are very or sort of well characterized from a safety standpoint. However, there are molecule-specific attributes that have led to, we believe have led to this ADA signal. In addition to focusing on sort of the standard safety aspects such as, you know, infection rates, etc., obviously, we'll be looking at immunogenicity as well, given that that's a key focal point. To your point on KOLs, that is something the KOLs now have asked a lot about. It should be noted that positive cohort, they still, you know, they still were kind of in that 40-ish% proteinuria reduction. I think it just remains to be seen if that reduction exposure will ultimately lead into some EGFR reduction that they'll show in the third quarter of this year, in the June-August time frame. Sure. To what degree is APRIL suppression correlated with, galactose-deficient IgA suppression versus nonspecific IgA suppression? Yeah. Maybe just repeat it for the webcast. Yeah. The relationship between total IgA reduction and Gd-IgA1 reduction, the pathogenic variant, we actually had a poster on this at ASN in November of last year, and you see a very high correlation, like R squared's above 99 between total IgA and serum IgA1. Although galactose-deficient IgA1 is considered the pathogenic variant, you really don't get any additional information in terms of predictivity of clinical responses than total IgA since they go together very closely. They're both knocked down to an equal degree. Is that what I understand? Yeah. That's right. Exactly. With the upcoming povotecicep data, just any expectations for that readout, and in particular, hypogammaglobulinemia focus among some folks, is that a real risk for the class, a real risk? How do you think about that? Yeah. Maybe I'll start, then Andrew can layer on. There was a hypogam signal, albeit in very low ends in the phase II for povotecicept, and I think a lot of naturally, there are a lot of questions that I think investors will be focused on that. We haven't seen that with the selective anti-APRIL, so we think that there could be a scenario where BAFF layering on top of APRIL. With full, you know, that sort of max 55% IgA, you typically see something like a 30% IgG reduction. When you layer on BAFF, that's just additive to what you would see. I think it could be a risk at higher doses. It's also worth noting that Alpine studied two doses in the phase II. They saw a very high infection signal at 240, and so we'll see if it's really just at that high dose that they see this hypogam signal. But as I mentioned before, we will be showing IgG as part of our phase 1 healthy volunteer readout to, you know, to hopefully demonstrate that we don't have that signal. I think to your point on the pove expectations, again, I think it remains to be seen. We wanna see those data. It could just be small ends. Yes, but obviously, there's an understandable focus on that. As far as the efficacy side, they did show a 56% absolute proteinuria reduction in phase II. It's hard to say. You see, you do see some variance, but if it's, if it's like Sivi, you know, you get sort of a, you know, 5%-ish placebo response. We would expect them to be in that, you know, 50-odd range. All right. If the phase one data look as we hope it will look by the end of the first half, the question really becomes how quickly can you get to market, right? When do you think you can start treating IgAN patients? When can you start a registrational trial? Next steps would be helpful. We've guided that we'll start our phase II study in the middle of this year. Our sort of base case assumption is what the most recently, you know, will soon to be unveiled phase III, for IgAN, which is povotacicept. They ran as a reminder, they ran a very small open label phase II. They took 6 patients at 36 weeks to the FDA before triggering their phase III. That's kind of a base case, because it's a very recent precedent. However, the FDA has asked that the NKF, the National Kidney Foundation, convene in April. This is gonna be a consortium of regulators, patients, sponsors, and KOLs to talk about potential ways to shorten the pathway for registration for some of these trials. I think that's in large part because there's a recognition that with this anti-APRIL or dual APRIL BAFF class, you're seeing a very early separation of the EGFR curves that you did not see in prior. Faster, we would obviously, you know, enable, we would want to exploit that as much as we possibly could. Adding on to the accelerated approval pathway, I guess some of again, question if it would still be viable or with these new therapies approved, if you'll have to use one of them as a comparator. What are your latest thoughts on that? We don't think there's much precedent for active controls in nephrology studies, and it does take significant time to be established as standard of care, beyond just initial accelerated approval of sibeprylimab, and approval's not available in most countries outside of the U.S. We think it's very unlikely to have an active comparator. In terms of accelerated approval, the most recent agents that have gone through phase reinitiation are the CD38, and they still have the same pathway available to them, 9 months proteinuria for accelerated approval, 2 years for EGFR. As Brad mentioned, we'll be active participants in this NKF workshop about defining novel IgAN strategies, and the goal is to make it more efficient rather than less efficient. We are confident, following that workshop and our interactions with the FDA that they will remain a very efficient pathway for development of JADE101 and IgAN. Great. In the last two or three minutes here, have to touch on 201, the afucosylated BAFFR antibody. You know, just, obviously, the Novartis' data are quite intriguing and they have the 6 ongoing phase IIIs, as you noted. You mentioned the improved half-life, but can you just elaborate on that bit, the differentiation versus Ianalimab, and the importance of that half-life in these patients? Yeah. What we've seen from Novartis' phase three data from Sjögren's is that Q4-week dosing showed better efficacy than Q12-week dosing, and the Q4 was really designed around BAFF receptor occupancy throughout that dosing interval, whereas Q12 really relied on extended B-cell depletion and slow recovery in humans. That informs us that to get the best efficacy out of this MOA, you really wanna drive BAFF receptor occupancy coverage. With JADE201 in non-human primates, we've doubled the half-life relative to Ianalimab, which will allow us to provide more sustained and robust receptor occupancy with an extended dosing interval with a convenient sub-Q dosing profile. The goal is not to only provide better convenience than Ianalimab, but potentially drive better efficacy through more sustained BAFF receptor occupancy. Great. What do you think you need to see in the phase I to have confidence to move forward into later stage registrational trials? I guess obviously, it's confirmation of the half-life, but what else will you be looking at? Yeah, it's a really biomarker-rich phase I first in human study as well. Not only will it be tolerability of the B-cell depleting mechanism, the pharmacokinetics showing extended half-life, but direct measures of BAFF receptor occupancy, and B-cell depletion, over time, which will enable us to define that profile of BAFF receptor occupancy through an extended dosing interval. As Brad mentioned, the phase I study is in RA patients really as the most efficient patient population to enroll for our first in human with an enhanced B-cell depleter. What we do know is that RA patients respond very quickly, therapeutically to B-cell depleters. Opportunistically, we are incorporating exploratory measures of efficacy, such as DAS28, looking at joint pain and swelling, to provide potentially even a greater characterization of JADE101 in its first in human study to set up for future development, in other autoimmune diseases. Great. Briefly here, since we're at time, I mean, that slide you have with all the indications, that's tens of billions, if not $100 billion-plus in terms of total market opportunity, right? Obviously, you guys have to focus, given your life cycle, and where JADE is at as a company right now. Are there a couple indications that you guys are comfortable calling out? Yeah. I mean, we, as I mentioned, we like the rheum and nephrology indications 'cause that's where we have in-house expertise. Like, ANCA-associated vasculitis is an indication where we think there's a high unmet need, it's there's a lot of biological rationale, and it's very, it's very commercially attractive. In the Novartis fast followers, there's still. I think there's still too much data that needs to be read out before we've kind of, you know, picked some of our, our favorites there. We think we'll let those data sort of mature competitively, but then also simultaneously, we're gonna characterize our own, you know, phase 1 data and then guide on our, go forward path, after that. Great. To close out, I'll ask you my favorite question. Just what do you believe is the most underappreciated aspect of the JADE story by investors? I personally think you guys are just kind of under the radar for some investors, but curious to get both of your thoughts on that. Yeah. I mean, I think with the lead program, I mean, I think this is a rising tide lifts all boats type of scenario. I mean, it is a very large potential commercial opportunity. We have now really practice-changing therapies for patients. We're really excited to be, you know, hopefully a participant in that market. You know, we think that as continued data mature on the positive side, we think that that'll hopefully, you know, translate to us, and we really wanna show some of those desirable attributes to have the best, you know, the sort of the best monoclonal antibody for IgAN patients. The rest of our pipeline, we're very excited about, of course. You know, a lot of... I think it's underappreciated because I think a lot of the focus, frankly and understandably, is on JADE101. I think that is probably the most underappreciated, but it's not, you know, it's, again, not entirely surprising. Andrew, I don't know if you have a different answer to that. No, I agree. Just to add, an exceptional team of experienced. Yeah ... drug developers to be able to effectively advance the three antibody, programs that we have. Wonderful. With that, Andrew and Brad, thank you so much for your time. Thanks everyone for coming. Have a great day.