Everyone, we're back again. We now have Jade Biosciences here for a fireside, CEO Tom Frohlich and CSO Andrew King for a fireside chat. Maybe I'll hand it over to Tom for a quick intro to the company, and then we'll get into the Q&A. Tom, over to you. Great, thanks Alex. Really appreciate the opportunity to connect with you. Also, this conference really focusing on I&I is just really nice to shine a light on this area. Yeah, so Jade, it's a really exciting time for Jade. We're a fairly young company. We got started just over a year ago, focused exclusively on developing best-in-class therapeutics for a number of different autoimmune diseases. We are founded based on three assets that we have access to from Paragon Therapeutics, which I guess many are familiar with. It's an antibody discovery company based in the Boston area. Really talented protein engineers who can develop extremely high affinity binding monoclonal antibodies against high-value targets. Of course, they have this expertise in half-life extension to be able to provide really thorough target coverage throughout the dosing interval, and also be able to provide best-in-class dosing, which is really important for patients. Our lead program is an anti-APRIL antibody. The first indication will be IGAN, an area where we're quite familiar. Andrew and I both came from Chinook Therapeutics. A lot of our team does as well. We have a lot of competency in that area. We're really excited by IGAN and continue to be. We think it's an extremely large market, over a $10 billion branded opportunity just in the U.S. alone. We have strong conviction that the APRIL class will really come to the forefront and be foundational therapy across all patients with the disease. A very big opportunity. Within the APRIL class, Jade 101 has all of the properties to become a best-in-class and actually therefore best-in-disease compound with best-in-class clinical activity and very convenient dosing schedules for patients. We're targeting one subcutaneous injection no more frequently than every eight weeks. Also exciting because we just got that program into the clinic. We announced dosing of the first cohort earlier this month. We're now officially a clinical stage company, which is always nice in the headline. We're moving really quickly towards that first-in-human readout in the first half of next year. Extremely important for us because in IGAN, it's extremely biomarker rich. We will be able to characterize Jade 101 quite fully just through that healthy volunteer study looking at biomarkers like IGA drops plus reductions in APRIL. Through that, we'll be able to understand really what is the dose and the dose interval and have high conviction that we are meeting that profile of best clinical activity. Really exciting time for us. Maybe super quickly, we just went public earlier this year. We closed a reverse merger to access the capital markets and concurrently brought in the financing, which gives us sufficient runway to advance our three programs through 2027. Very exciting time for us. Maybe setting the stage a little bit more, how would you describe the current IGAN treatment landscape and how do you think that's going to evolve over the next two to five years? Yeah, it's a really interesting time for IGAN with several approved therapies over the last couple of years. Today, most patients still get an ACE inhibitor or an ARB, some sort of RAS inhibition just right out of the gate after diagnosis. Quite often, if they're not meeting proteinuria targets, physicians still treat to lowering proteinuria, even though the ultimate goal is to preserve kidney function as measured by EGFR. If they're not meeting proteinuria goals, they'll add on other agents like SGLT2s, which are quite commonly used now. Endothelin receptor antagonists were just recently approved as well, and they get layered in. If those things aren't working, they'll go to immunosuppressants like steroids. That unfortunately does not really stabilize kidney function in most patients. That's why it is such an exciting time with all these emerging B-cell therapies. We really actually think to that question, how is the landscape going to evolve? We really think those agents are going to move to the forefront. Actually, the new proposed updates to the KDIGO guidelines, which should actually be official in the next month or so, really do highlight that. They bifurcate treatments into two different areas. One is kind of local nephroprotection in the kidneys, and that's where a lot of those agents with things like hemodynamic effects, like the ACE inhibitors, the SGLT2s, the ERAs will be classed. Now they're really saying that every patient should be on an agent that is proven to reduce pathogenic IGA. That's why the selective anti-APRILs will really move to frontline therapy. The way that we see it evolving is upon diagnosis, every patient will still get that ACE ARB because they work, they nephroprotect, they're cheap, and they're safe. They'll also concurrently get an anti-APRIL as well on top of that. Very exciting time. Only if they don't hit those really ambitious thresholds in proteinuria, which is sort of the second big takeaway from the new updates to the KDIGO guidelines, they're lowering those proteinuria thresholds down to 0.5 g a day. If you're not hitting those thresholds, that's when further treatment should be added. Yeah, that makes sense. I guess you both have had a front row seat to the BAFF-APRIL development space for the last few years as well. I guess what have we learned about BAFF and APRIL in IGAN and sort of what it means to be the best sort of drug in that class? Yeah, we have learned that every agent that does hit APRIL has dramatic reductions in proteinuria, can stabilize eGFR, and also does deplete that pathogenic IgA. That's the reason why we think these will be foundational therapies. What we do know, though, is APRIL is really driving all of the efficacy there. We've seen very similar results across the APRILs and the dual APRIL BAFFs, really showing us that there is not added benefit in IGAN specifically of adding BAFF. We've seen older therapies like CD20s that were really used and actually selective BAFF inhibitors like blisibimod that actually had no effect in IGAN at all. No reductions in IgA, no effect on proteinuria lowering. We strongly believe that all of the efficacy in these agents is being driven by APRIL and that the selective anti-APRILs will actually preferentially be used because you don't get that longer-term depletion of the broader B-cell compartment. In IGAN, as you know, the patients are diagnosed in their 20s and 30s and need decades and decades of treatment. We think physicians and patients are going to select the more specific immunomodulator. If the benchmarks are truly sibeprenlimab and zygelimab now for a later stage pure anti-APRILs, what does it mean to develop a best-in-class anti-APRIL? Can you talk about kind of those key design elements that you pulled out for 101? Yeah, Andrew, do you want to take that one? Yeah, happy to. As Tom mentioned, we've seen a remarkable disease-modifying impact of the anti-APRILs, pathogenic IgA, proteinuria reductions, as well as eGFR stabilization. What we've learned from sibeprenlimab and zygelimab is that the best clinical activity in IGAN can be safely achieved with full APRIL suppression throughout the dosing interval. These first-gen anti-APRILs can really only achieve this profile with high IV dosing, which is not feasible to transition to convenient subcutaneous dosing long-term in IGAN patients. This is largely a result of potency limitations combined with pronounced target-mediated drug disposition that limits the pharmacological activity of these first-gen agents. To us, a best-in-class monoclonal provides full APRIL suppression, capturing the full disease-modifying efficacy available to this MOA through an extended dosing interval. IGAN patients are typically young, in their 20s and 30s when they're diagnosed, requiring decades of therapy. We do believe reducing the patient burden by minimizing the number of injections required per year also adds value to the MOA. What we've done with Jade 101 to design around these challenges is to select an ultra-high binding affinity anti-APRIL. Jade 101 has femtomolar affinity to APRIL, approximately 50 femtomolar KD, which is 750-fold higher than sibeprenlimab and 2,000-fold higher than zygelimab. This potency will allow us to fully suppress APRIL at lower plasma concentrations. We've also incorporated half-life extension into the Fc with YTE modifications to again provide extended exposures, time above those trough target levels to fully suppress APRIL, but do it with a single subcutaneous injection, no more frequently than every eight weeks. Why do you need such a potent molecule here? Can you also talk about the importance of epitope selection as well? Yeah, so we need to be able to fully suppress APRIL throughout this extended dosing interval. To do that, potency is a big advantage. What we've seen from our analyses of the publicly available clinical data for the first-generation agents is that their ability to suppress IgA, the concentrations for which they can do that at, is totally dependent on their binding affinity to APRIL. The lower the binding affinity, the greater the ability to suppress APRIL and produce those large and sustained reductions in IgA. Jade 101 also has a novel epitope. It does functionally block the binding of APRIL to BCMA and TACI, its two receptors, but does it with a unique mechanism of action. With trimeric proteins like APRIL, when monoclonal antibodies bind them, there is the potential for large immune complex formation because each APRIL can bind three monoclonals and each monoclonal can bind two APRILs. Through this daisy chaining-like effect, you can produce large immune complexes. Large immune complexes provide risks associated with immunogenicity. They also can be rapidly cleared by the circulation, producing this rapid nonlinear clearance characterized by target-mediated drug disposition or TMDD. The novel epitope, which we've selected Jade 101 for, prevents the formation or doesn't allow for the formation of large immune complexes by its binding mechanism. With this profile, we believe not only it reduces the risk of immunogenicity, it has mitigated the pronounced TMDD that was observed in the first gen, which allows us to again fully inhibit APRIL down to low plasma concentrations through an extended dosing interval. What has historically been shown from non-human primates to human translation, both in IGAN with IgA suppression, but also from the YTEs to humans? Yeah, we're really fortunate with NHPs being a translational model system for both the pharmacokinetics of YTE-mediated half-life extended antibodies, as well as for the biomarker-rich response to the anti-APRIL MOA. From a PK perspective, what we typically see is a two to four-fold increase in half-life going from non-human primates to humans. On average, that's about a three-fold increase. We have reported a 27-day half-life of Jade 101 in non-human primates. That sets up well for an extended half-life using those metrics in humans. Also, what we see from a free APRIL reduction and an immunoglobulin response downstream, IgA, IgM, and IgG reductions, the non-human primate has been highly consistent to what's been observed in Healthy Volunteers. We do feel like our differentiated preclinical non-human primate PKPD profile is predictive of a differentiated profile in the clinic. Further, from a translation perspective, the Healthy Volunteer PKPD is highly consistent with what you ultimately see in IGAN patients. We do feel like this biomarker-rich response, as Tom mentioned, in Healthy Volunteers will allow us to define our dose and dose interval to move forward into later stage trials in IGAN patients. What does this translation of greater APRIL suppression look like clinically? I think if you look at the sibeprenlimab IB data, like what are we talking about in terms of like clinically significant differences versus the phase three data set? Yeah, the CIVI data you mentioned from phase two is the best characterization of the dose response on APRIL inhibition in IGAN. In that study, they used three separate doses versus placebo, 2, 4, and 8 mg per kilogram IV. So body weight-adjusted IV dosing. They observed dose-dependent reductions in APRIL across that dose range, such that at the high dose, they essentially achieved full APRIL suppression in all patients for the 52-week treatment period. Importantly, that was safe and well tolerated. Safety profile was indistinguishable across those groups, and there was no increased risk of infection versus placebo control, even at that high dose with full APRIL suppression. That full APRIL suppression, in addition to being safe and well tolerated, produced the best clinical response. The greatest magnitude of proteinuria reduction quantitatively, it was about 7% greater than the mid-dose, the 4 milligram per kilogram dose. Importantly, as Tom said, relative to the updated KDIGO guidelines, there was greater than twofold the number of patients at that high dose that achieved the definition of clinical remission. So proteinuria less than 0.3 g per day, back to within the normal range, which is the new preferred target range in those updated KDIGO guidelines. When Otsuka transitioned from this phase two data set into phase three, shifting to subcutaneous flat dosing, they disclosed that they approximated that middle dose, really probably most likely for convenience reasons, the maximum amount of drug that could fit into a single 2 mL syringe once a month. We believe they've left efficacy on the table. With Jade 101, a more potent half-life extended antibody, we really want to replicate that high dose efficacy that sibeprenlimab achieved in phase two to deliver best-in-class clinical activity with the most convenient dosing schedule. Does this translate to difference in eGFR stability over time? I guess if you look back at the proof of concept data, all of these drugs seem to basically stabilize eGFR. If there's differences this large in proteinuria, but eGFR is flat, does it really matter? Yeah, it's a great point, Alex. Over a two-year time point with all of these agents, you will likely see a stabilization of EGFR. Clinicians are worried about 10, 15, 20 years. When you look at all the epidemiological data, it's quite clear that patients with residual levels of proteinuria, essentially above 0.5 g a day, are at longer-term risk of progression. The 10, 15-year rates are actually getting pretty high of kidney failure. That's really why clinicians are now looking to these lower proteinuria thresholds, getting patients below 0.5 g a day, and then ideally below 0.3 g a day back into the normal range to really minimize or eliminate that long-term risk of EGFR loss. You are going to have your phase one data next year. What does the path towards pivotal development look like in IGAN? Is it going to change at all now that we're going to have BAFF-APRILs or APRILs on the market? What does the path look like here? Yeah, we will have that data in the first half of next year. As we mentioned, it's such critical data for us because with this mechanism, you see that time course of, you know, first you get these big drops in APRIL, followed by these drops in IgA. That in healthy volunteers, that reads through directly and what you anticipate seeing in patients in terms of proteinuria drops and then eGFR stabilization. It's such a well-defined and well-behaved mechanism that that phase one readout, as Andrew said, will give us our dose and dose interval and allow us to feel conviction that we're hitting that best clinical activity profile. It also lets us move into later stage trials into patients very efficiently. We haven't provided exact guidance on exactly what that will look like. We do need to interact with regulators. Our phase one trial is in New Zealand, so we haven't had interactions with the FDA yet. We do think it's a very efficient development pathway. We're envisioning something likely similar to what Alpine did with povetacicept, so a short targeted open-label phase two, where we can get proof of concept there in patients in terms of proteinuria reductions. They use that to trigger a pivotal study to move really, really quickly. Something along those lines is likely our base case. There might be also opportunities to kind of shortcut that a little bit if we get the data and the responses that we would like. In terms of the new agents and how that impacts our pivotal study thinking, Andrew, do you want to walk through that with kind of availability of other agents out there? Yeah, it is an important consideration now to conduct trials in the presence of these available therapies. It will be important to allow patients to be on stable and optimized background therapy at the discretion of the nephrologist. That will most likely be RAS inhibitors, SGLT2 inhibitors, and/or endothelin receptor antagonists. They still remain at risk for progressive kidney function loss per guidelines. We do think we'll be able to conduct a placebo-controlled study on top of that optimized background therapy. We don't think we will at this stage need to go head-to-head against an anti-APRIL since none are yet approved. Their first approvals will be accelerated approval. It will take some time to move to kind of that standard of care where you may need to go head-to-head. We think the timing is actually great for our program because the first-generation anti-APRILs, anti-APRIL BAFFs have completed their enrollment through their phase three program. We believe there will be strong demand for these agents in the clinical trial setting because of their disease-modifying impact. Also, it's important to recognize that approval is largely restricted to the United States at this time. IGAN is a global disease with higher prevalence in Asian countries where the agents are not going to be available in the near term. We do think we can leverage the excitement around the impact of these agents. We typically only need 300 to 400 IGAN patients total for a development program. We feel there's a very efficient way to execute that trial, even in the setting of the availability of these new agents. Any worry that accelerated approval via proteinuria won't be on the table anymore? As Tom mentioned, we haven't talked to the FDA yet, but we'll engage in these conversations. We don't think so. We think the pathway has been working well for IGAN. The first few agents that have been approved under this pathway have confirmed their EGFR benefit. With the anti-APRIL mechanism, the treatment effects on both proteinuria and EGFR are larger than those first set of agents that have gone through. We also see in other nephrology indications, the cardiorenal division is more seriously contemplating proteinuria as a surrogate, including in FSGS. West Barcentin is under review based on novel proteinuria thresholds in FSGS. We feel like they're getting more comfortable rather than less comfortable with proteinuria as a surrogate. We will have these conversations, as Tom highlighted, through our FDA interactions. Yeah, so beyond IGAN, there's also potential for using an anti-APRIL mechanism elsewhere. What does that look like for you? Is that a core part of what you're thinking about next? We definitely do want to explore other potential indications. This mechanism, as I mentioned, is so well behaved. It's well tolerated. We do think IGAN is a large opportunity, but we will explore potentially pending positive phase one data. Other potential indications like IGM-driven diseases, as you know, Alex, APRIL inhibition lowers IgA dramatically. It preserves mostly IgG, but then gets these large drops in IgM. We do think there is potential use in things like multifocal motor neuropathy. That's probably an underappreciated indication. We know argenx is looking at a C2 inhibitor there. We think this is an opportunity to go upstream to that pathogenic driver of disease, as well as a couple of other IGM-driven diseases like anti-MAG neuropathy or cold agglutinin disease. Pending market conditions, we may have a basket trial there if we get positive phase one data. We know Otsuka is looking at a subset of Sjogren's as well with sibeprenlimab. We will be keeping a very close eye on that because once again, we have a more potent, better dosed APRIL inhibitor. If there are some positive signs there, we believe that's a significant opportunity as well. Beyond IGAN and APRIL, what should we expect for the disclosure around Jade 201? What can you say now and when should we expect to learn more? Yeah, we're not saying much. As you know as well, for competitive reasons, we don't want other agents popping out of the woodwork to compete with us until we're a bit closer to the clinic. We are on track and we do anticipate getting that program initiated, the phase one in the first half of next year. We have nominated a development candidate. Those activities are ongoing to enable that start. We likely will disclose that target before the end of the year to support that. We have said it's a B-cell target that can go after a number of different systemic autoimmune diseases. You mentioned your cash flow in a way. Can you talk a little bit about what's embedded in those assumptions? We closed the last quarter with $221 million, and we have guided that that will fund operations on the three prog through 2027. Very importantly, through that phase one data in the first half of next year for Jade 101, but as well provide funding for Jade 201 and 03. Great. Tom, Andrew, appreciate it. Thanks for joining us. Great. Thanks, Alex. Thanks a lot, Alex. Hey everyone, we're back. We'll get into the Q&A. Tom, over to you. Great, thanks Alex. Really appreciate the opportunity to connect with you. Also, this conference really focusing on I&I is just really nice to shine a light on this area. Yeah, so Jade, it's a really exciting time for Jade. We're a fairly young company. We got started just over a year ago, focused exclusively on developing best-in-class therapeutics for a number of different autoimmune diseases. We are founded based on three assets that we have access to from Paragon Therapeutics, which I guess many are familiar with. It's an antibody discovery company based in the Boston area. Really talented protein engineers who can develop extremely high affinity binding monoclonal antibodies against high-value targets. Of course, they have this expertise in half-life extension to be able to provide really thorough target coverage throughout the dosing interval and also be able to provide best-in-class dosing, which is really important for patients. Our lead program is an anti-APRIL antibody. The first indication will be IGAN, an area where we're quite familiar. Andrew and I both came from Chinook Therapeutics. A lot of our team does as well. We have a lot of competency in that area. We're really excited by IGAN and continue to be. We think it's an extremely large market, over a $10 billion branded opportunity just in the U.S. alone. We have strong conviction that the APRIL class will really come to the forefront and be foundational therapy across all patients with the disease. A very big opportunity. Within the APRIL class, Jade 101 has all of the properties to become a best-in-class and actually therefore best-in-disease compound with best-in-class clinical activity and very convenient dosing schedules for patients. We're targeting one subcutaneous injection no more frequently than every eight weeks. Also exciting because we just got that program into the clinic. We announced dosing of the first cohort earlier this month. We're now officially a clinical stage company, which is always nice in the headline. We're moving really quickly towards that first-in-human readout in the first half of next year. Extremely important for us because in IGAN, it's extremely biomarker rich. We will be able to characterize Jade 101 quite fully just through that healthy volunteer study looking at biomarkers like IGA drops plus reductions in APRIL. Through that, we'll be able to understand really what is the dose and the dose interval and have high conviction that we are meeting that profile of best clinical activity. Really exciting time for us. Maybe super quickly, we just went public earlier this year. We closed a reverse merger to access the capital markets and concurrently brought in the financing, which gives us sufficient runway to advance our three prog through 2027. Very exciting time for us. Maybe setting the stage a little bit more, how would you describe the current IGAN treatment landscape and how do you think that's going to evolve over the next two to five years? Yeah, it's a really interesting time for IGAN with several approved therapies over the last couple of years. Today, most patients still get an ACE inhibitor or an ARB, some sort of RAS inhibition just right out of the gate after diagnosis. Quite often, if they're not meeting proteinuria targets, physicians still treat to lowering proteinuria, even though the ultimate goal is to preserve kidney function as measured by eGFR. If they're not meeting proteinuria goals, they'll add on other agents like SGLT2s, which are quite commonly used now. Endothelin receptor antagonists were just recently approved as well, and they get layered in. If those things aren't working, they'll go to immunosuppressants like steroids. That unfortunately does not really stabilize kidney function in most patients. That's why it is such an exciting time with all these emerging B-cell therapies. We really actually think to that question, how is the landscape going to evolve? We really think those agents are going to move to the forefront. Actually, the new proposed updates to the KDIGO guidelines, which should actually be official in the next month or so, really do highlight that. They bifurcate treatments into two different areas. One is kind of local nephroprotection in the kidneys, and that's where a lot of those agents with things like hemodynamic effects, like the ACE inhibitors, the SGLT2s, the ERAs, will be classed. Now they're really saying that every patient should be on an agent that is proven to reduce pathogenic IgA. That's why the selective anti-APRILs will really move to frontline therapy. The way that we see it evolving is upon diagnosis, every patient will still get that ACE ARB because they work, they nephroprotect, they're cheap, and they're safe. They'll also concurrently get an anti-APRIL as well on top of that. Very exciting time. Only if they don't hit those really ambitious thresholds in proteinuria, which is sort of the second big takeaway from the new updates to the KDIGO guidelines, they're lowering those proteinuria thresholds down to 0.5 g a day. If you're not hitting those thresholds, that's when further treatment should be added. Yeah, that makes sense. I guess you both have had a front row seat to the BAFF-APRIL development space over the last few years as well. I guess what have we learned about BAFF and APRIL in IGAN and sort of what it means to be the best sort of drug in that class? Yeah, we have learned that every agent that does hit APRIL has dramatic reductions in proteinuria, can stabilize eGFR, and also does deplete that pathogenic IgA. That's the reason why we think these will be foundational therapies. What we do know, though, is APRIL is really driving all of the efficacy there. We've seen very similar results across the APRILs and the dual APRIL BAFFs, really showing us that there is not added benefit in IGAN specifically of adding BAFF. We've seen older therapies like CD20s that were really used and actually selective BAFF inhibitors like plazibamod that actually had no effect in IGAN at all. No reductions in IgA, no effect on proteinuria lowering. We strongly believe that all of the efficacy in these agents is being driven by APRIL and that the selective anti-APRILs will actually preferentially be used because you don't get that longer-term depletion of the broader B-cell compartment. In IGAN, as you know, the patients are diagnosed in their 20s and 30s and need decades and decades of treatment. We think physicians and patients are going to select the more specific immunomodulator. If the benchmarks are truly sibeprenlimab and zygelimab now for a later stage pure anti-APRILs, what does it mean to develop a best-in-class anti-APRIL? Can you talk about kind of those key design elements that you pulled out for 101? Yeah, Andrew, do you want to take that one? Yeah, happy to. As Tom mentioned, we've seen a remarkable disease-modifying impact of the anti-APRILs, pathogenic IgA, proteinuria reductions, as well as eGFR stabilization. What we've learned from sibeprenlimab and zygelimab is that the best clinical activity in IGAN can be safely achieved with full APRIL suppression throughout the dosing interval. These first-gen anti-APRILs can really only achieve this profile with high IV dosing, which is not feasible to transition to convenient subcutaneous dosing long-term in IGAN patients. This is largely a result of potency limitations combined with pronounced target-mediated drug disposition that limits the pharmacological activity of these first-gen agents. To us, a best-in-class monoclonal provides full APRIL suppression, so capturing the full disease-modifying efficacy available to this MOA through an extended dosing interval. IGAN patients are typically young, in their 20s and 30s when they're diagnosed, requiring decades of therapy. We do believe reducing the patient burden by minimizing the number of injections required per year also adds value to the MOA. What we've done with Jade 101 to design around these challenges is to select an ultra-high binding affinity anti-APRIL. Jade 101 has femtomolar affinity to APRIL, approximately 50 femtomolar KD, which is 750-fold higher than sibeprenlimab and 2,000-fold higher than zygelimab. This potency will allow us to fully suppress APRIL at lower plasma concentrations. We've also incorporated half-life extension into the Fc with YTE modifications to again provide extended exposures, time above those trough target levels to fully suppress APRIL, but do it with a single subcutaneous injection, no more frequently than every eight weeks. Why do you need such a potent molecule here? Can you also talk about the importance of epitope selection as well? Yeah, so we need to be able to fully suppress APRIL throughout this extended dosing interval. To do that, potency is a big advantage. What we've seen from our analyses of the publicly available clinical data for the first-generation agents is that their ability to suppress IgA, the concentrations for which they can do that at, is totally dependent on their binding affinity to APRIL. The lower the binding affinity, the greater the ability to suppress APRIL and produce those large and sustained reductions in IgA. Jade 101 also has a novel epitope. It does functionally block the binding of APRIL to BCMA and TACI, its two receptors, but does it with a unique mechanism of action. With trimeric proteins like APRIL, when monoclonal antibodies bind them, there is the potential for large immune complex formation because each APRIL can bind three monoclonals and each monoclonal can bind two APRILs. Through this daisy chaining-like effect, you can produce large immune complexes. Large immune complexes provide risks associated with immunogenicity. They also can be rapidly cleared by the circulation, producing this rapid nonlinear clearance characterized by target-mediated drug disposition or TMDD. The novel epitope, which we selected Jade 101 for, prevents the formation or doesn't allow for the formation of large immune complexes by its binding mechanism. With this profile, we believe not only it reduces the risk of immunogenicity, it has mitigated the pronounced TMDD that was observed in the first gen, which allows us to again fully inhibit APRIL down to low plasma concentrations through an extended dosing interval. What has historically been shown from non-human primates to human translation, both in IGAN with IgA suppression, but also from the YTEs to humans? Yeah, we're really fortunate with NHPs being a translational model system for both the pharmacokinetics of YTE-mediated half-life extended antibodies, as well as for the biomarker-rich response to the anti-APRIL MOA. From a PK perspective, what we typically see is a two to four-fold increase in half-life going from non-human primates to humans. On average, that's about a three-fold increase. We have reported a 27-day half-life of Jade 101 in non-human primates. That sets up well for an extended half-life using those metrics in humans. Also, what we see from a free APRIL reduction and an immunoglobulin response downstream, IgA, IgM, and IgG reductions, the non-human primate has been highly consistent to what's been observed in Healthy Volunteers. We do feel like our differentiated preclinical non-human primate PKPD profile is predictive of a differentiated profile in the clinic. Further, from a translation perspective, the Healthy Volunteer PKPD is highly consistent with what you ultimately see in IGAN patients. We do feel like this biomarker-rich response, as Tom mentioned, in Healthy Volunteers will allow us to define our dose and dose interval to move forward into later stage trials in IGAN patients. What does this translation of greater APRIL suppression look like clinically? I think if you look at the sibeprenlimab IV data, like what are we talking about in terms of like clinically significant differences versus the phase three data set? Yeah, the CIVI data you mentioned from phase two is the best characterization of the dose response on APRIL inhibition in IGAN. In that study, they used three separate doses versus placebo, 2, 4, and 8 mg per kilogram IV. So body weight-adjusted IV dosing. They observed dose-dependent reductions in APRIL across that dose range, such that at the high dose, they essentially achieved full APRIL suppression in all patients for the 52-week treatment period. Importantly, that was safe and well tolerated. Safety profile was indistinguishable across those groups, and there was no increased risk of infection versus placebo control, even at that high dose with full APRIL suppression. That full APRIL suppression, in addition to being safe and well tolerated, produced the best clinical response. The greatest magnitude of proteinuria reduction quantitatively, it was about 7% greater than the mid-dose, the 4 milligram per kilogram dose. Importantly, as Tom said, relative to the updated KDIGO guidelines, there was greater than twofold the number of patients at that high dose that achieved the definition of clinical remission. So proteinuria less than 0.3 g per day, back to within the normal range, which is the new preferred target range in those updated KDIGO guidelines. When Otsuka transitioned from this phase two data set into phase three, shifting to subcutaneous flat dosing, they disclosed that they approximated that middle dose, really probably most likely for convenience reasons, the maximum amount of drug that could fit into a single 2 mL syringe once a month. We believe they've left efficacy on the table. With Jade 101, a more potent half-life extended antibody, we really want to replicate that high dose efficacy that sibeprenlimab achieved in phase two to deliver best-in-class clinical activity with the most convenient dosing schedule. Does this translate to difference in eGFR stability over time? I guess if you look back at the proof of concept data, all of these drugs seem to basically stabilize eGFR. If there's differences this large in proteinuria, but eGFR is flat, does it really matter? Yeah, it's a great point, Alex. Over a two-year time point with all of these agents, you will likely see a stabilization of EGFR. Clinicians are worried about 10, 15, 20 years. When you look at all the epidemiological data, it's quite clear that patients with residual levels of proteinuria, essentially above 0.5 g a day, are at longer-term risk of progression. The 10, 15-year rates are actually getting pretty high of kidney failure. That's really why clinicians are now looking to these lower proteinuria thresholds, getting patients below 0.5 g a day, and then ideally below 0.3 g a day back into the normal range to really minimize or eliminate that long-term risk of EGFR loss. You are going to have your phase one data next year. What does the path towards pivotal development look like in IGAN? Is it going to change at all now that we're going to have BAFF-APRILs or APRILs on the market? What does the path look like here? Yeah, so we will have that data in the first half of next year. As we mentioned, it's such critical data for us because with this mechanism, you see that time course of, you know, first you get these big drops in APRIL, followed by these drops in IgA. That in healthy volunteers, that reads through directly in what you anticipate seeing in patients in terms of proteinuria drops and then eGFR stabilization. It's such a well-defined and well-behaved mechanism that that phase one readout, as Andrew King said, will give us our dose and dose interval and allow us to feel conviction that we're hitting that best clinical activity profile. It also lets us move into later stage trials into patients very efficiently. We haven't provided exact guidance on exactly what that will look like. We do need to interact with regulators. Our phase one trial is in New Zealand, so we haven't had interactions with the FDA yet. We do think it's a very efficient development pathway. We're envisioning something likely similar to what Alpine did with povetacicept, so a short targeted open-label phase two where we can get proof of concept there in patients in terms of proteinuria reductions. They use that to trigger a pivotal study to move really, really quickly. Something along those lines is likely our base case. There might be also opportunities to kind of shortcut that a little bit if we get the data and the responses that we would like. In terms of the new agents and how that impacts our pivotal study thinking, Andrew, do you want to walk through that with kind of availability of other agents out there? Yeah, it is an important consideration now to conduct trials in the presence of these available therapies. It will be important to allow patients to be on stable and optimized background therapy at the discretion of the nephrologist. That will most likely be RAS inhibitors, SGLT2 inhibitors, and/or endothelin receptor antagonists. They still remain at risk for progressive kidney function loss per guidelines. We do think we'll be able to conduct a placebo-controlled study on top of that optimized background therapy. We don't think we will at this stage need to go head-to-head against an anti-APRIL since none are yet approved. Their first approvals will be accelerated approval. It will take some time to move to kind of that standard of care where you may need to go head-to-head. We think the timing is actually great for our program because the first-generation anti-APRILs, anti-APRIL BAFFs have completed their enrollment through their phase three program. We believe there will be strong demand for these agents in the clinical trial setting because of their disease-modifying impact. Also, it's important to recognize that approval is largely restricted to the United States at this time. IGAN is a global disease with higher prevalence in Asian countries where the agents are not going to be available in the near term. We do think we can leverage the excitement around the impact of these agents. We typically only need 300 to 400 IGAN patients total for a development program. We feel there's a very efficient way to execute that trial, even in the setting of the availability of these new agents. Any worry that accelerated approval via proteinuria won't be on the table anymore? As Tom mentioned, we haven't talked to the FDA yet, but we'll engage in these conversations. We don't think so. We think the pathway has been working well for IGAN. The first few agents that have been approved under this pathway have confirmed their eGFR benefit. With the anti-APRIL mechanism, the treatment effects on both proteinuria and eGFR are larger than those first set of agents that have gone through. We also see in other nephrology indications, the cardiorenal division is more seriously contemplating proteinuria as a surrogate, including in FSGS. West Barcentin is under review based on novel proteinuria thresholds in FSGS. We feel like they're getting more comfortable rather than less comfortable with proteinuria as a surrogate. We will have these conversations, as Tom highlighted, through our FDA interactions. Yep. Beyond IGAN, there's also potential for using an anti-APRIL mechanism elsewhere. What does that look like for you? Is that a core part of what you're thinking about next? We definitely do want to explore other potential indications. This mechanism, as I mentioned, is so well behaved. It's well tolerated. We do think IGAN is a large opportunity, but we will explore potentially pending positive phase one data. Other potential indications like IGM-driven diseases, as you know, Alex, APRIL inhibition lowers IgA dramatically. It preserves mostly IgG, but then gets these large drops in IGM. We do think there is potential use in things like multifocal motor neuropathy. That's probably an underappreciated indication. We know argenx is looking at a C2 inhibitor there. We think this is an opportunity to go upstream to that pathogenic driver of disease, as well as a couple of other IGM-driven diseases like anti-MAG neuropathy or cold agglutinin disease. Pending market conditions, we may have a basket trial there if we get positive phase one data. We know Otsuka is looking at a subset of Sjogren's as well with sibeprenlimab. We will be keeping a very close eye on that because once again, we have a more potent, better dosed APRIL inhibitor. If there are some positive signs there, we believe that's a significant opportunity as well. Beyond IGAN and APRIL, what should we expect for the disclosure around Jade 201? What can you say now and when should we expect to learn more? Yeah, we're not saying much. As you know as well, for competitive reasons, we don't want other agents popping out of the woodwork to compete with us until we're a bit closer to the clinic. We are on track and we do anticipate getting that program initiated, the phase one in the first half of next year. We have nominated a development candidate. Those activities are ongoing to enable that start. We likely will disclose that target before the end of the year to support that. We have said it's a B-cell target that can go after a number of different systemic autoimmune diseases. You mentioned your cash flow in a way. Can you talk a little bit about what's embedded in those assumptions? Yeah, we closed the last quarter with $221 million, and we have guided that that will fund operations on the three programs through 2027. Very importantly, through that phase one data in the first half of next year for Jade 101, but as well provide funding for Jade 201 and 03. Great. Tom, Andrew, appreciate it. Thanks for joining us. Great. Thanks, Alex. Thanks a lot, Alex.