All right. Hi, everyone. Thanks for joining us at the Wells Fargo Healthcare Conference. My name is Sadia Rahman, one of the biotech analysts here at Wells Fargo, and it is a pleasure to introduce Jade Biosciences for our next session. From Jade, we have CEO Tom Frohlich, President of R&D, Andrew King, and CMO Edward Conner. Thanks for being here. Before we get into Q&A, I will hand it over to you for any opening remarks. Great. Thanks so much, and thanks to you and the whole team for hosting us. It has been a really productive, great to get a chance to get back into the season after an amazing summer. Really pleased to talk a little bit about Jade. We are a fairly new company, just started two years ago, looking to develop best-in-class therapies across a number of different autoimmune diseases. We have three assets that we have licensed in from Paragon, which I am sure many people are familiar with, a protein engineering company that really does discovery across a number of different monoclonal antibodies. Our lead program is JADE101. It is an anti-APRIL, going after IgA nephropathy. Extremely exciting program. IgA nephropathy is an area of large unmet need. We believe it is around a $20 billion market opportunity in the U.S. alone, and we believe the anti-APRIL class is really going to become dominant and foundational therapy for patients at risk of disease progression. JADE101 has a really good opportunity to become the best in disease molecule. We recently reported out some phase I data in June of this year, showing very deep and profound reductions in IgA, the key pathogenic marker of potential disease progression, approaching 70%, the largest ever drop seen with a single dose in healthy volunteers with any agent. Really showing that JADE101, due to its potency, can capture the maximal activity available to the mechanism. Also, those reductions were sustained for up to 12 weeks, really showing that we can have maintenance of the disease with a single injection just every three months. An extremely promising profile that we are really excited to move forward. We are currently in a phase II trial with JADE101, reporting out that data next year in 2027, moving quickly towards that key milestone for us as a company. We are not waiting for that data set to advance a phase III study. We are actually working hard to initiate a phase III. We plan to dose our first patient in a phase III in the first half of 2027, and move very quickly towards a data readout there, and commercialization, so we can try to capture as much of that large market as possible. We also have JADE 201, which is just in a phase I study right now. That is an anti-BAFF-R compound that is a B cell depleting agent that is applicable to a number of different autoimmune diseases. Really anything where rituximab is standard of care, JADE201 has a chance to improve treatment there. We are following the footsteps of ianalumab, which is an asset at Novartis that is currently in six different phase IIIs, reported out positive data in Sjögren's last year, as well as second-line ITP, and has a number of different readouts coming out over the next 12 months that will help inform our strategy there. We are currently in a phase I study in rheumatoid arthritis patients, and planning to read out that data in 2027 as well. Our third program, which we just recently disclosed, is JADE301. It is an anti-interferon beta, and the lead indication there is for dermatomyositis, a very severe disease that affects both the muscle and the skin. We are just going to go into a phase I healthy volunteer study with that program, and looking forward to reading out some data on that one in 2027 as well. Very active build on the pipeline and the team. We have a great team that we have recruited. A number of us actually worked together at Chinook Therapeutics before. Andrew and I were both there essentially since the founding of that company. We have managed to pull across a number of the best talents, so a lot of development capabilities. We are well-funded as well. We have completed a few financings in the last year, which really funds our entire pipeline through to the fourth quarter in 2028, past all of those milestones that I talked about. Very exciting time for us as a company. Yeah, definitely. Just wanted to dig into the phase I data that you presented a couple of months ago, and Climb Bio, a competitor, also presented some phase I data, I believe, last week. Just talk about how the data sets compare between the two molecules. Broadly, they look similar on pharmacodynamic effects and kinetics, and they also are targeting a similar dosing interval and injection volume, I believe. When you compare the data, are there any differences that you would highlight in biomarker reductions? Any potential for meaningful differentiation between these molecules? Yeah. It is a great question. We remain very confident that with JADE101, we have the best profile given those large levels of IgA reductions and the ability to sustain that for 12 weeks. Andrew, do you want to talk a little bit about the details and the differentiation there? Yeah. When we designed JADE101, our goal was to deliver the full disease-modifying efficacy of B-cell modulation in IgAN with a convenient infrequent dosing schedule. We really wanted to optimize two specific parameters. One was to improve the potency over the first generation agents, and the second was to half-life extend, to be able to spread out that dosing interval. We feel like our phase I healthy volunteer data really demonstrated both of those attributes, where we had an extended half-life relative to sibeprenlimab by about 2.6-fold, and demonstrated really remarkable in vivo IgA-lowering potency, which reflects the high binding affinity to APRIL that JADE101 was selected for. As a result, we see these rapid, large reductions in IgA really reaching the biological max effect you can see with a single dose of a selective APRIL inhibitor. Our assessment of the CLIMB data suggests they've also effectively half-life extended their molecule similar to JADE101, but have done so with a compound that has lower binding affinity. They really haven't been able to incorporate that improved potency, which we think is really critical to be able to drive early and rapid IgA reductions to maximum levels, and do so consistently across the broader population. Whereas with a lower binding affinity molecule, there is potential for less complete IgA suppression and more variability, and we think that's played out in the data. As Tom mentioned, really confident about the profile of JADE101, and excited to develop it as a best-in-class asset. Mm-hmm. Is there anything in the phase I data that you would highlight that differentiates IgA reduction? You talked about maybe kinetics of IgA reduction? Yeah. I think it's both the depth, the duration, and the consistency of the IgA reduction at the 700 mg dose of JADE101, which is our planned induction dose, taken forward into phase II and phase III. We saw rapid IgA reductions that reached 70% decrease from baseline and were sustained for 12 weeks following dose before recovery beyond that. We saw highly consistent responses across the healthy volunteer participants included in the study, with very small error bars. With CLIMB, they demonstrated IgA reductions that maxed out in the 55%-ish range, including at their 320 mg maintenance dose. Higher doses of CLIMB, either as two separate 320 mg doses two weeks apart or a single 480 mg dose, didn't appear to be able to break through that mid-50% floor that they achieved. So more like those first-generation agents with sibeprenlimab that appeared to require repeat dosing over time in IgAN patients to approach the IgA reductions observed with JADE101 with a single dose. We also saw higher variability in the response of IgA with CLIMB across all dose levels, which would be consistent, potentially, with the lower binding affinity not being able to completely neutralize all biologically relevant APRIL present in the tissues, particularly the mucosal immune system, to drive local IgA production and mucosal immunity. Got it. Based on the phase I data with JADE101, it appears that Q8W at the lower dose, the 350 mg, provides more complete biomarker coverage for the duration of the dosing interval. How confident are you that the induction dose with 700 mg, with Q12W maintenance with the lower dose can provide the same control that you're looking for? Yeah. Really confident in the ability of the Q12W maintenance to maintain those initial large IgA reductions that are produced by the induction dose. Our PK/PD modeling suggests similar IgA reductions are maintained with either Q8W or Q12W dosing, giving us further confidence that the Q12W maintenance interval provides the full disease-modifying efficacy of IgA lowering for JADE101. An important consideration here is that the maintenance dose is administered on top of the loading dose, so target-mediated drug disposition, which has been very impactful to the first generation anti-APRIL agents, is fully saturated at the time of that first maintenance dose. So it's really building a very strong PK/PD foundation to then maintain with a low infrequent dose over time. Got it. Compared to the first generation agents, just elaborate on the PD findings from phase I and how they could translate into better efficacy, whether it's on proteinuria or something else. Yeah. What we've seen with the first generation agents across trials is that early IgA reduction, just at eight weeks, is highly predictive of the proteinuria reduction you ultimately see in IgAN patients at that nine-month time point, with greater IgA reductions associated with greater proteinuria reduction. We also see with the first-generation agents that IgA reduction takes time to get to those peak levels with repeat dosing and is accompanied by deepening proteinuria reduction over time. Our goal with JADE101, with this ultra-potent molecule and this loading dose, is to rapidly drive IgA down as quickly as possible to maximum levels to potentially bring that efficacy forward from what we've seen with the first generation agents. The potential for larger reductions in proteinuria at that nine-month time point, which has been the initial focus on Accelerated Approval for the first generation agents. Importantly, that has the potential to be associated with achieving greater rates of targets of proteinuria thresholds in the KDIGO guidelines. More patients below 0.5 g per day, more patients below 0.3 g per day. The potential to differentiate by this potent molecule and the loading dose strategy to bring the proteinuria reductions deeper and earlier, which is really what nephrologists treat to, because on a visit-to-visit basis, it's hard to track eGFR, and it's really an initial focus on reducing proteinuria, getting the disease into remission, and having high confidence of improved long-term kidney outcomes. Mm-hmm. As far as the phase II readout, what would you like to see to conclude that there is differentiation? Are we looking at a nine-month time point? Are we looking earlier? Just talk about the timeline relative to the phase III initiation and whether there might be a selection of a single dosing interval versus both, or do you see value in proceeding with both dosing intervals? Yeah. Sorry. I know that's a lot. No, that's a good question, though. Maybe I'll start with the phase II, and then we can talk about the phase III plans. We initiated that phase II in May of this year, so we are actively enrolling patients there. It is an open-label trial, enrolling up to 30 patients, so 15 in a Q8 cohort and 15 in a Q12W cohort, following the dosing regimen that Andrew described with a 700 mg loading dose and starting those regimens at week four. We haven't predetermined what the data cut will be that we'll present next year. But we do want to make sure that we're presenting a meaningful data set with enough patients to be able to look at things like IgA reductions. Are we replicating in patients what we saw in healthy volunteers? And then what level of proteinuria reduction are we getting? We'll probably follow something similar to a lot of the first-generation agents that showed a handful of patients, like 8- 10, at a 36-week time point, because that has been the comparator. But we'll provide more updates as we get them and then be able to disclose that next year. In terms of expectations, we really want to see just replicating what we anticipate seeing from that healthy volunteer study, which is really good, deep, robust reductions in IgA and robust reductions in proteinuria. We're not going to wait for that data to initiate the phase III. We are moving extremely quickly. We do have a lot of confidence and conviction out of that phase I data set that it did characterize that dose profile. We have the utmost confidence in that Q12W dosing arm, and we believe that's going to be the go-forward dose that we go to commercialize. But we did design the phase III with those two dose arms to really enable us to go extremely quickly. There is an expectation with some global regulators that you do some dose range finding. So we do think having those two arms really enables us to move really quickly before we get a bigger, meaningful phase II data set to initiate that study. So we will carry that phase III forward with those two dose arms. Got it. Good job covering all parts of that question. Recently we're seeing some of the eGFR readouts from the APRIL BAFF agents, and they're setting a pretty high bar for efficacy. What are your thoughts on the eGFR data that we're seeing and the apparent consistency between anti-APRIL versus BAFF APRIL agents? Do you think all of these agents reach some threshold on APRIL suppression where there is an eGFR ceiling at two years? And could there be any differences that emerge if we follow patients longer? Do you want to take that one? Yeah. It has been truly remarkable to see the disease-modifying impact of these agents, really stabilizing eGFR over extended periods of time, out through two years now in placebo-controlled phase III trials and two and a half years in open-label phase II trials. eGFR stabilization is really the best you can hope to achieve— Yeah. —in chronic kidney disease because the decrease in eGFR we observe at baseline is a result of a loss of nephron number, which can't be regenerated. It's really stabilizing and maintaining the kidney function that we have. That really is the bar to match in a phase III trial. It would be very difficult to exceed that. What we know long term, and this is not just over a two-year phase III clinical trial, but in the lifetime of an IgAN patient who's diagnosed typically in their 20s and 30s, and requires therapy not for two years, but for decades, potentially lifelong, is that residual proteinuria is the greatest predictor of future progression. Although we don't think there's a large opportunity to differentiate on eGFR in a clinical trial setting, there is, as I mentioned earlier, the potential to demonstrate faster, deeper proteinuria reduction, greater rates of those clinical remission-type endpoints to give the nephrologist, give the patient the highest confidence that their long-term kidney outcomes through their lifetime, not just over the two years of a clinical trial, will be very promising. Mm-hmm. Just digging a little deeper on the eGFR data, just curious what you make of the increases or slight increases in eGFR out to two years. Is that consistent with that initial resolution or inflammation at that time point? Normally I've heard that, in the past when KOLs would talk about it, they would say, "Normally we would expect a decline of 1 ml per year in healthy individuals." Just curious what you think about that complete stabilization or even a slight increase. Yeah. It is interesting that consistently across programs, we're seeing this small increase in eGFR relatively early after initiating an APRIL inhibitor. It would be consistent with the potential resolution of some acute inflammation that's being driven by these immune complexes that are hemodynamically lowering eGFR, and you've resolved that, and you've returned normal kidney function in the absence of that inflammatory response. Because we are seeing numeric increases of eGFR above baseline that are sustained through that 2+ year time point. So maybe that's the likely explanation. The age-related decline that you would expect in these 40-plus-year-olds of 1 ml per minute per year is being hidden in that acute phase resolution. Okay. Makes sense. You've talked about BAFF potentially adding some risk without adding efficacy in IgAN. Is there anything you're seeing in the biomarker data, particularly IgG depth and kinetics, that points to this potential liability for BAFF? Yeah. So what we have seen on the efficacy side is no additional clinical benefit from adding BAFF inhibition. We are not seeing deeper IgA, Gd-IgA reductions, deeper proteinuria, hematuria resolution. As we have discussed, selective APRIL inhibition is sufficient for full eGFR stabilization. BAFF inhibition does impact a broader set of B cells than APRIL inhibition, which selectively targets plasma cells. So it does introduce the potential for broader immunosuppression and infection risk. The safety data sets are still relatively immature over short periods of follow-up following Accelerated Approval. But we have seen some hints in the phase II data and emerging phase III data of potentially numerically higher rates of upper respiratory tract infections that last for a longer period of time than in placebo-treated patients. For povetacicept in particular, from phase II, we have seen cases of hypogammaglobulinemia, which does increase the risk of immunosuppression. So it will be interesting to watch these data sets mature over time. Without evidence so far of increased clinical benefit of adding BAFF inhibition, what does the long-term safety profile look like with extended duration of treatment? Mm-hmm. Yeah, and it is interesting that IgG seems to continue to decline slowly, even out past two years for BAFF APRILs or even anti-APRILs. Just curious if you think that with chronic dosing, we could see increased cases of hypogam or infections with these agents, if there might be the need for a dosing holiday, not long-term chronic dosing. Is there anything you would watch for in the phase III presentations, for example, povetacicept, the two-year data, that could indicate these risks? Yeah. We have limited long-term biomarker data for this class to review. We have got the small open label zigakibart selective APRIL inhibitor study out through two and a half years. It actually does seem like IgG does stabilize at a maximum biological response of about 35% decrease from baseline, whereas you do continue to see some incremental decline in IgA and Gd-IgA1 over that period of time. So there does appear to be a flaw in IgG reduction that you get with selective APRIL inhibition. As long as you select for patients that can tolerate that 35% or so IgG reduction before they achieve clinically significant hypogammaglobulinemia, it appears to be safe and well-tolerated long term. We are particularly interested to see the povetacicept phase III data because of some of those early signals from phase II. Here, you are combining APRIL inhibition, which gives you that 30%-35% reduction in IgG with BAFF inhibition, which, in the case of Benlysta, a selective BAFF inhibitor, does reduce IgG alone. It will be interesting to see that combination effect with longer duration of treatment. Yeah, and I think a lot of people are going to be watching for that data, but we also just hear anecdotally from clinicians and patients that if you are going to be hitting a broader compartment of the immune system, then you would want to see some benefit in order to do that. We do think there is going to be a preference emerge over time for the selective anti-APRILs because you are seeing all of the same benefits on efficacy with a more narrow targeting. Mm-hmm. Got it. Wanted to switch to the pivotal trial plans with JADE101. Obviously the treatment landscape is changing quickly in IgAN. Multiple new approvals, including potentially a third B-cell agent this year, and they are showing remarkable eGFR efficacy. This could make placebo-controlled trials harder to do, particularly in the U.S. and China. There could be new guidance on pivotal trials coming soon. What would you expect from that guidance, and would you expect that to come before you finalize your phase III plans? Do you want to take that one, Ed? Yeah, sure. So there are There was recently the National Kidney Foundation assembled a group of treating physicians, industry, and the FDA. I think there was full acknowledgment that doing two-year placebo-controlled studies at this point, when you have agents coming on the market that are disease-modifying, these patients are inexorably losing kidney function that can't be recovered. So there's broad agreement that one year placebo control is sufficient. Now I think combine that with the sibeprenlimab two-year eGFR data, and you're seeing that the one-year estimate holding there is sufficient. More where we think they are headed, and this was reaffirmed at the recent GlomCon conference in Maui by the deputy director of that division, was that one year endpoint is sufficient, and that it would be expected to include both proteinuria and eGFR as well. That consortium did also evaluate, do you need an active comparator or not in the studies? I think there was agreement unanimously that that just isn't feasible in a rare disease, in a trial of this size. So, we think just a one-year trial, as Ed described, versus standard of care is going to be suitable for approval. Mm-hmm. Interesting. On the commercial opportunity, we're seeing the early numbers from the sibeprenlimab launch. How does that validate the market for B-cell agents in IgAN? Do you expect that trajectory to continue, or could uptake in the community settings require more time? That's a great question. I think TBD a little bit, but we are very encouraged by the initial uptake of sibeprenlimab, and it reflects what we're hearing from clinicians about the demand for these disease-modifying agents. They saw 2,000 patient starts in the first six months of this year and really have increased their revenue guidance for the year, showing that really strong demand. We do know that there's about 8,000 nephrologists in the U.S. About 10% of them are specialists, working more at tertiary centers that really focus on primary glomerulonephropathies like IgA nephropathy. Those are the ones probably prescribing at the outset, where they really are familiar with the class, they understand the KDIGO guidelines and the need to treat with these types of agents. So those are probably that first wave that you're seeing through. To your point, though, there are a lot of community-based nephrologists that work more in dialysis centers and more with generalized CKD, that aren't up to speed on these types of agents and probably do need some market development and education, and that might take some time. But we are hearing feedback that as soon as people are exposed to this class of medications, that there's a high willingness to prescribe. So we do think that there is a really big market potential for this class of medications. In fact, enough to support multiple entrants. We are very encouraged that there's an increased focus to really maximizing that clinical activity. There's an increased awareness that you need to have something extremely convenient for patients. So we do think the profile of JADE101 is really well positioned to capture a lot of that market. Mm-hmm. On that convenience, there is some differentiation between the first three agents that have launched. What should we be watching to understand how important more convenient dosing is in this market to validate that JADE101 could have an advantage even with a later entry? Yeah. It's a good question. With the agents that are coming to market now, so sibeprenlimab is dosed Q4W. Atacicept, which was just recently approved, is once weekly, so we'll have to look at what is the share uptake versus those two. Vertex's product is going to be once every four weeks, which should be approved later this year. So I think looking at the share dynamics there will be informative. But we have done fairly extensive market research, including a conjoint analysis where we're looking at what variables of frequency is really driving uptake. We do see that a strong choice driver for IgA nephropathy is that longer dose interval. So we're quite confident that a quarterly dose will command a lot of share in the marketplace. Mm-hmm. Got it. All right, switching to JADE 301, which you unveiled the mechanism recently. It is a selective IFN beta, and you plan to advance it for dermatomyositis. IFN beta is elevated in DM, but I think alpha might also be elevated, and anifrolumab blocks the shared receptor. What led you to IFN beta rather than the broader interferon pathway? Is there evidence that blocking IFN beta alone can be efficacious? Yeah. Do you guys want to take that? Sure. Yeah, in terms of the signature itself, I think it is very strongly skewed towards interferon beta. I would have to understand what the alpha signature is because what we have seen, and I think the dazukibart data validates that, is that particularly in the gene signature analysis they did in their skin biopsies, looks like it is primarily driven by interferon beta. I think the problem, of course, with interfering alpha as well is that on the viral immunology side, you run into increased risks not only of worsening viral infections, but also viral reactivation as well. I think broadly speaking, is that worth the additional potential safety liabilities when it appears to be predominantly interferon beta driven. Mm-hmm. Got it. Are you planning to advance this as a monotherapy? Is there a broader applicability for this as monotherapy, or would you consider combining it with JADE301 or 201? No, we see its high value in it as a monotherapy. Again, if you look at, we are all familiar with the ripretinib data, but if you look numerically both at CDASI, which is a measure of efficacy in the skin, dazukibart is significantly better than what was seen in ripretinib. The TIS, or Total Improvement Score, is more based on the neuromuscular outcomes. Ripretinib did see improvements there, I think about a 14.5 increase. The dazukibart study was underpowered, but numerically, they saw around 19.5. Again, showing that on both sides of the equation, whether it is skin or neuromuscular, they were outperforming it as well. From that perspective, in our view, a monotherapy makes sense. We do not see the value add that would occur in applying an additional molecule. Got it. You are planning to present pre-clinical data at the end of the month or early next month. What could we see in that pre-clinical data at EADV to maybe help understand the potential of the mechanism? Do you want to go over that? Yeah. It is really a detailed characterization of the pre-clinical profile of JADE301, so including binding affinity, potency, non-human primate, half-life, to really understand the differentiated profile relative to dazukibart, the Pfizer Inc agent, that, as Ed mentioned, has showed strong phase II proof of concept, but limited by high IV frequent dosing, providing a significant patient burden. The goal with JADE101 is to deliver the full efficacy of the interferon beta mechanism, with infrequent subcutaneous dosing profile. Mm-hmm. Maybe in the last few minutes, I will switch to JADE201. You will have phase I data in 2027. What could we learn from that data in RA patients on B-cell depletion, BAFF-R occupancy, and how could it help prioritize indications, or are we also looking at the ianalumab data in additional readouts to help with that? Yeah. I think that is a great point. Just a reminder to the audience, JADE201 targets BAFF receptor, following in the footsteps of ianalumab, which is a program that is at Novartis, currently in multiple phase IIIs, had positive Sjögren's data and ITP data. We will see readouts from systemic sclerosis and lupus nephritis. All of those data sets will help inform our indication, selection, and prioritization, but we also see a number of other opportunities where Novartis likely did not go for strategic or pipeline prioritization reasons, where rituximab is standard of care. There is some first and class indications we are exploring as well. The first step is, as you mentioned, really getting that phase I rheumatoid arthritis data, where we will be able to really understand the safety tolerability of JADE201, but look at some very important biomarkers that will help inform how differentiated are we from ianalumab. Namely, looking at B-cell depletion dynamics and very importantly, receptor occupancy of BAFF-R, because that will really help us understand what is the dose and the dose interval that will be carried forward for JADE201. We will get that data next year, and then we will make more decisions on which indications to go into once we understand the profile a little bit better. Mm-hmm. Just wanted to get your thoughts on ianalumab data in Sjögren's. Do you think that the limited efficacy delta there reflects more the trial design and trial conduct rather than the true potential of the mechanism? Yeah. It's an unfortunate result, I would say, because in Sjögren's, the average patient had an ESSDAI score at baseline of around 12, and with ianalumab treatment, they managed to get it down to six, which is actually quite a great improvement on ESSDAI. The unfortunate part was placebo had around a 4.5% or 5% drop, so the delta versus placebo and the treatment effect was not large. It was a positive trial, but just barely positive from a p-value standpoint. But when we talk to clinicians, rheumatologists, they're really excited by that 6-point improvement in ESSDAI. And we know that the FDA gave them Fast Track designation, so they'll get approved, and we think there'll be really broad, rapid uptake. We'll have to look closely at the way that trial was designed and the inclusion criteria for the patients to see how do we feel about advancing in an indication with that type of a p-value. But right now, the way that we understand it is unlikely we would do something there alone, as JADE. Potentially, we could partner JADE201 with someone who would want to invest in Sjögren's. But we see some other indications with a clearer shot at demonstrating a significant result in a shorter timeframe as probably being a priority for us at JADE. Mm-hmm. Just last question. You talked about the current cash runway. How are you thinking about investing in JADE301 and IgAN versus exploring combinations of these molecules that you have, and investing in the individual assets? Yeah. So we're well-financed into Q4 of 2028 across all three programs, and that includes getting JADE101 into the phase III and getting that program well underway. Getting the phase II data for JADE301, JADE201 getting the phase I RA data, as well as a subsequent study with JADE201, and then JADE301 passed a phase I trial as well, so multiple catalysts. So we're lucky at this stage, we don't have to think too much about prioritization one versus the other. But obviously, a big value driver for us is going to be JADE301 and that phase III trial and really making sure we execute on that flawlessly. But tons of room for value creation ahead. All right. Great. Well, we're out of time, but thank you so much for joining. Appreciate all the insights. Excellent. Thanks so much. Thank you