... Are Are we on? There we go. So, welcome to the Cantor Global Healthcare Conference. I'm Pete Stavropoulos, a biotech analyst at Cantor. With us, we have Jade Biosciences, and I'm pleased to introduce Tom Frohlich, CEO, and Andrew King, CSO. Two individuals who were part of a company we used to cover before they were acquired by Novartis, Chinook. So, welcome, and thank you for taking the time. Starting off, can you just give an introduction of yourselves and provide a brief synopsis of Jade Biosciences? Yeah, happy to, and thanks so much for hosting us, Pete, and the whole Cantor team. It's been a really great, great day to kick off the fall after a really nice summer. So yeah, Tom Frohlich, I'm the CEO here. Andrew King is our Chief Scientific Officer and Head of R&D, as you mentioned. You also mentioned that the both of us actually came from Chinook Therapeutics, which was acquired by Novartis in 2023. I took a little bit of time off after Chinook, so did Andrew. He actually stumbled upon a group called Paragon that was developing antibodies across a number of different targets, and they have special talent in developing very high-affinity binding molecules with half-life extension. Andrew said, "Oh, let's start a company based off of a couple of assets out of Paragon." We had a strong desire to work together again. We thought it kind of got cut off a little bit too early in the Chinook days and really wanted to get the band back together with a couple of key development leaders. Really quickly formed a company about a year ago, Jade Biosciences, as you mentioned, really focused on developing best-in-class therapeutics across a number of different autoimmune indications. We have three assets that we have access to from Paragon. The lead asset, which I'm sure we'll talk a lot about today, is an anti-APRIL. The initial indication is for IgAN. Really excited by that class of molecules. They have disease-modifying potential. They can lower proteinuria to a very large extent and stabilize kidney function, which is the ultimate goal for patients with kidney disease. Very excited as well, yesterday we announced dosing of our first cohort in healthy volunteers, so we're now officially a clinical stage company, which is a really nice achievement in a short time. So we're moving forward very efficiently with that and looking forward to data in the first half of 2026. We have two other assets we're not talking too much about. The second asset, though, what we will say is we're aiming to get into the clinic in the first half of next year. Third asset is about a year behind that. So a really promising pipeline across autoimmune indications, and we're also relatively well-financed, too. We feel like we're in a fortunate position. We closed a reverse merger in April, and through a convertible note and a PIPE financing we did in that reverse merger, we raised a total of $300 million, which enables us to fund that portfolio through 2027. So we feel like we've got great assets, a good mission, an excellent team, and we're well-financed, so really excited about what's in the future for Jade. Awesome. Anything to add, Andrew, or...? No, I think Tom covered it really well. Excited to be here partnering with him on Jade. Very good. So just a broad question, given both your background, spanning both, large pharma and small biotech, what are the key learnings from, both of these types of experiences that you're applying to Jade, to make it successful and, create shareholder value? Yeah, I'd actually love that question, 'cause actually we talk about this quite a bit because both Andrew and I spent a bunch of years in large pharma, Andrew at AbbVie in their Renal Research Division. I worked across a number of different commercial positions at Merck and J&J. And I think big pharma, I think it's kind of slagged a lot, even though they don't need to be. I think that you can really learn there. It's an amazing training ground to see what can you do exceptionally well, and they go into depth in every facet of drug development and commercialization, and you can really see what good looks like. The nice thing about spending a bunch of years there is you see, you know, what is the full spectrum of activity in each different area, and you can really learn, like, what is the best practice. What's great about then moving to a smaller biotech, though, is you can say, "Okay, which element is actually required to do at that 100%, to make sure you're doing it exceptionally well. But then what areas can you actually cut a few corners and do at 60% and get sort of the same result?" So I feel like both of us have that experience of seeing, like, what is the full spectrum, understanding what are, like, the really important components to focus on in drug development, discovery, and commercialization, and then where can we move a little bit faster and a little bit leaner to be more efficient and more flexible. Andrew, agree? I agree. It's really this great training ground that you can't replicate anywhere else. You're working side by side with functional experts in every domain, and I think that experience sets you up really well for the broader roles you get in biotech to most efficiently advance programs. All right, so I won't get into it. I think I'm gonna ask it a little bit later, but my assumption is, you know, where you can cut corners and perhaps leverage, you know, data from other studies or knowing how something can happen, you know, it can affect, let's say, a certain biomarker, and cutting corners there. That's exactly right. So understanding where can you get a high degree of conviction with maybe a smaller amount of data. So in clinical development, for sure, you can do that. Also, things like market research, like in pharma, you would do a 300-physician conjoint analysis to make sure you understand what potential share there is, where maybe doing that with, like, 20 phone calls with KOLs can give you the same- ... like, or 80% of that result, which is kind of good, good enough. Okay. Yeah. So, you know, there's been a lot of activity in the B-cell-driven autoimmune space in various indications, including autoantibody-driven kidney disease, neuromuscular diseases, and others. And different approaches are being taken, B-cell depletion, B-cell modulation, targeting complement. And, you know, you're focusing in on B-cell modulation. Tell us about your candidate 101, and what drove you to focus your efforts on APRIL? You know, was it your experience at Chinook, or the clinical data rolling out for this mechanism, or combination? Yeah, absolutely. There is a lot of excitement around B-cell therapies, especially in IgAN. And actually, this has been long brewing. Like, from our time at Chinook, we kind of looked into our crystal ball and tried to understand how is the market evolving specifically for IgAN. And what—even when we were looking sort of back four or five years ago, we realized that some agents were more acting downstream in the kidney, really on kind of a local nephroprotection, whereas there's this other whole class of medications that can actually take away the root cause of the disease, that pathogenic IgA that's actually causing the insults to the kidney in the first place. So as we thought about that, we thought, well, you know, you should protect the kidney, but also, if you can take away the cause of disease, that, that's what's really gonna be transformational here. So we had a strong interest in that selective anti-APRIL. We know that the IgAN market's big. It's a $10 billion-plus opportunity, and we saw because of that move, that the APRIL inhibitors were gonna move to frontline therapy and become foundational for essentially every patient with IgAN. We're really excited that the KDIGO guidelines are really reflecting that. The recently proposed updates, which should be adopted in the next couple of months, really do suggest that every patient should be on an agent that depletes pathogenic IgA. We thought the APRIL class was gonna come out as really the winning class because they get all of the efficacy with a very selective immunomodulation, even more selective than the APRIL BAFF inhibitors, in terms of sparing B cells more broadly. Within the APRIL class, though, we are behind a couple of other agents. I guess there's Sibeprenlimab at Otsuka, and then zigakibart, the old Chinook, now Novartis compound, are several years ahead of us. But we believe there's an opportunity to have a best-in-class therapeutic with JADE 101 because Sibeprenlimab, which is the most advanced asset, is actually leaving efficacy on the table. They've gone from body weight-adjusted IV dosing in phase II into a flat sub-Q format in phase III, and they aren't fully maximizing the efficacy available to the mechanism. So with JADE 101, our goal is to have complete inhibition of APRIL throughout the dosing interval to get higher levels of clinical activity. And we can do that with our molecule, which has the half-life extension, and do that with less frequent dosing. So we're aiming for one injection, sub-Q injection, no more frequently than every eight weeks. So we believe that we can capture a significant share of that IgAN market, even though we're a couple of years behind where Sibeprenlimab is. You asked if we're learning from zigakibart. Like, absolutely. There's a lot of publicly available information out there, and we're using that to really guide our clinical development pathway, use things like biomarkers to try to go extremely efficiently and quickly. All right, so, you know, where did you actually come across this asset? I mean, you mentioned, Paragon. And, what were the characteristics that you were sort of looking for in an anti-APRIL? You mentioned a couple, but are there others? And, in other words, you know, what's the target product profile that you're aiming for? Andrew, do you want to take that? Yeah, JADE 101 was discovered in a de novo antibody discovery campaign from our partners at Paragon Therapeutics, exceptional antibody discovery experts and protein engineers, largely trained at Merck. And the TPP we were looking for was really a single sub-Q injection that could deliver the full disease-modifying efficacy available to the APRIL MOA, no more frequently than every eight weeks. And what we saw is the properties that eluded the first-generation anti-APRILs that precluded them from delivering this profile were really around binding affinity to APRIL. We wanted to identify an agent with superior binding affinity. We wanted to mitigate this target-mediated drug disposition that was very limiting for the dosing and dose interval for the first-generation anti-APRILs. And because IgAN patients are young, otherwise healthy, typically diagnosed in their twenties and thirties, we wanted to deliver the most convenient, infrequent dosing schedule, so we wanted to incorporate half-life extension into the antibody. So really deliver an anti-APRIL monoclonal antibody with best-in-class properties. Can you just touch a little bit more on the TMDD, and how these, you know, you're avoiding these high molecular weight complex formation? You know, just help us understand, you know, what are the consequences to actually forming these high molecular weight complexes, and how is Jade actually, JADE 101 avoiding this? Yeah, so target-mediated drug disposition is very prominent in the PK profiles of the first-generation anti-APRILs, both Sibeprenlimab and zigakibart. And that's characterized by this rapid nonlinear clearance below a certain plasma concentration threshold, which is associated with the loss of pharmacological activity. So you'll lose APRIL suppression, and IgA returns back towards baseline. We hypothesized that that was driven by large molecular weight complex formation. APRIL is a trimeric protein, so it allows three different anti-APRIL monoclonal antibodies to bind to each APRIL, and each antibody can bind two APRILs. So through this daisy chaining-like phenomenon, you can produce large molecular weight complexes, which are rapidly cleared from the circulation, resulting in this nonlinear clearance and loss of activity. In our screening campaign for the selection of JADE 101 as our lead, we specifically assessed the ability of our leads to avoid the formation of large immune complexes, and JADE 101 was selected with a novel epitope that had this property, and what we observed in our non-human primate PK/PD studies was really significant mitigation of that TMDD effect, such that you maintain slow linear clearance for extended durations well below where you lose activity with those first-generation agents. I mean, I know you're not going to tell me the exact epitope, but how are you actually avoiding the daisy chain? You know, do you have a Fab or you have the arms of the antibody, and you know, how are these epitopes being sort of shielded from one trimeric complex to another? Yeah, it's very subtle differences in epitopes, and it can be the orientation that the antibody attacks that epitope, which precludes it from forming large molecular weight complexes. It's not possible to empirically predetermine which antibodies will have this property, and it was really part of this extensive screening campaign in collaboration with Paragon, both through in vitro immune complex formation, but as well as in vivo non-human primate PK/PD screening to ensure we had the adequate properties that not only prevented immune complex formation but still functionally and completely blocked APRIL signaling. Okay. And, you know, you just mentioned non-human primate. You have conducted a PK/PD study, so how translatable are that data to, you know, especially on, based on a YTE antibody, translatable to humans? Yeah, the non-human primate has been very translatable for both the YTE pharmacokinetics but also through the biomarker-rich response to the APRIL mechanism of action. For YTE half-life extended antibodies, you typically see a 2x- 4x increase in half-life, when scaling from non-human primates to humans. And that gives us confidence, given our 27-day non-human primate half-life, that we will be able to deliver our target product profile of a sub-Q injection no more frequently than every eight weeks. But beyond just the half-life translation, we do consistently see with APRIL suppression an immunoglobulin profile characterized by deep reductions in IgA and IgM, with lesser effects on IgG, and that's also been highly translatable from monkey to human. So combined, we feel really excited about our healthy volunteer study, which we announced, as Tom mentioned. The first cohort has been enrolled now, and we believe that this profile will be translatable to humans. Okay. And, you know, you did present data at ERA earlier this year. In one of the experiments, you know, you looked at the PD profile, specifically IgA levels of Sibe versus 101, and this included a derivative of Sibe, where you put it onto the YTE Fc backbone. You know, when considering the doses and sort of comparing 101 doses and the outcomes, you know, what does the data sort of suggest? Yeah, so what we saw with wild-type Sibeprenlimab is a half-life of about seven days, an APRIL reduction, IgA reduction for about 28 days. Pretty typical of a non-half-life extended IgG in monkey. When we half-life extended Sibe, we got about 2x increase in both half-life and duration of IgA reduction, all at 30 milligrams per kilogram. When we compared head-to-head with JADE 101, our novel ultra-high-affinity, half-life extended anti-APRIL, we actually saw a 4x increase in half-life versus Sibeprenlimab, kind of highlighting you can't just put YTE on any antibody scaffold and get a effectively half-life extended antibody, and you really need this in vivo PK/PD screening to select the optimal antibody clone. With that 4x longer half-life, we also saw IgA reductions sustained beyond 100 days following a single intravenous dose. In fact, we also tested a lower, 7.5x lower dose of JADE 101 at four milligrams per kilogram, and it outperformed both Sibeprenlimab and YTE half-life extended Sibeprenlimab at that 30-milligram per kilogram dose from both the PK as well as IgA reduction, so this gives us confidence that we can deliver what Sibeprenlimab was unable to do, that full efficacy available to the MOA, with a single infrequent dosing schedule. Okay. So you just mentioned that you initiated the phase I. So I understand, you know, the purpose is to determine PK/PD profile. You know, since this is an extended half-life molecule, how often will you actually be taking samples from these subjects and for what duration? So how many doses are these patients going to get? Yeah, we... So, we have disclosed there's going to be four cohorts, 32 patients, eight per cohort, six and two in terms of active to placebo. We have disclosed it's a year-long study, and very typically, we're going to be taking a lot of measurements in the early days to really understand what the PK is looking like, safety, and then understand those biomarkers, as we mentioned. And we will likely... Well, we will have an interim readout in the first half of 2026. All right. Sort of, you know, what... I mean, obviously, we look at IgA biomarkers, but what else will you be looking at to sort of tie it back to the back to the go-forward doses and potential efficacy? Yeah, so this is where this trial is actually pretty different than a lot of healthy volunteer trials because IgAN is so biomarker-rich, and as Andrew pointed out, you can translate what you see in healthy volunteers to patients. And because we are following Sibeprenlimab and zigakibart and then the two dual APRIL BAFFs, we can really see what is the correlation between drops in free APRIL, IgA reductions and then what we anticipate seeing in terms of efficacy. And as we pointed out, our goal is to replicate that high dose of Sibeprenlimab they had in their IV study that they can't replicate with sub-Q. They just can't feasibly get to those dosages. What they saw was full suppression of APRIL throughout the entire dosing interval, and so that's what we're gonna be really looking at to guide what is the dose that we select for JADE 101, and then very importantly, actually, what is the dose interval? So we'll be able to see if we're hitting that target profile of eight weeks. And if we do see eight weeks of complete APRIL reduction, we'll understand we have that profile of really best-in-disease dosing, but then also that we're gonna hit that clinical activity that Sibeprenlimab had at their high IV dose that they can't do with their sub-Q. So it's really that free APRIL depth and duration that we're gonna be using for picking the dose and dose interval. All right, so you just mentioned data in 1H 2026 or interim data. What do you expect to show? Is it gonna be just SAD data, MAD data? It is just a single ascending dose. I think, Andrew always says with these YTE half-life extended drugs, the beauty of it is you're almost getting a MAD because there's such prolonged exposure. So with a SAD, we should be able to get enough information to allow us to move forward very quickly into patients. Are you saying skip a MAD or...? Yeah, most likely. We won't do MAD in healthy volunteers. Got it. Yeah. and this is a sub-Q formulation, the phase I, or IV? Correct, it's a sub-Q. All right. So, what are some of the key learnings from Sibe, the phase II and the phase III trials in IgAN, as well as zigakibart studies, that sort of inform your clinical development strategy for 101, especially regarding patient selection and concomitant drug use? Over to you. Yeah, so what, what we've seen with the first-generation anti-APRILs is really strong treatment effects on proteinuria, eGFR stabilization, across a variety of studies, including those that enrolled cohorts solely in the United States, those that primarily enrolled cohorts in Asia, and then global phase III clinical trials. The treatment effects are strong in this IgAN patient population at risk for progressive kidney function loss, despite optimized standard of care treatment with renin-angiotensin system inhibitors. We've also seen that early trials where SGLT2 inhibitor uptake was relatively low and recent trials where SGLT2 inhibitor uptake is quite high, have also delivered very similar and consistent, robust treatment effects. So that's very encouraging for the class, that this high-risk IgAN patient population at risk for progression on background standard of care is highly responsive to the anti-APRIL mechanism. What we're really interested in learning, which we haven't seen yet, is the subgroup analyses of these trials, particularly the ongoing phase III studies, and we're particularly interested to see if there's a subset of IgAN patients that are even more responsive than the average, and whether it's baseline proteinuria, eGFR, time from diagnosis, or perhaps even biopsy histological criteria that predict response to APRIL. This is one of the advantages of not coming first and being able to learn from the first programs that can provide us scientific insights to help define our clinical development program to optimize the potential to deliver strong top-line data. You sort of were first, but it got acquired. That's right. All right. How are you thinking about Filspari, right? So it's approved. It's available in these IgAN patients, as well as atrasentan. Congratulations on that one as well. I mean, you know, patients are gonna start getting onto these drugs. Would you incorporate them into your studies, future, or...? Yeah, I do think it's important that we deliver an IgAN program in the setting of contemporary therapy, to demonstrate additional benefit above and beyond what's currently available, so we haven't designed our phase II or phase III trials or guided on them, but I would imagine that it will be high-risk patients despite whatever background supportive therapy their nephrologist feels appropriate, so that will be RAS inhibitors and/or SGLT2 inhibitors and/or endothelin receptor antagonists, as long as that therapy is stable for at least 12 weeks coming into the trial, so these will be at-risk patients despite those available therapies in need of a disease-modifying treatment that depletes pathogenic IgA. Okay. So, you know, I don't know if you actually said this, if you said this before, but, you know, these were my thoughts, and you sort of validated them earlier on, in the beginning of our discussion. You know, what's your sort of strategy going forward after the healthy volunteer data? You said a phase I-B. You didn't say phase I-B, but you said a MAD in patients with IgA nephropathy. You know, so the degree of biomarker changes, you know, such as Gd-IgA, is known to be associated with proteinuria changes, you know, which is the primary endpoint in registrational studies. So, you know, will you leverage that data just to move forward, press forward straight into a phase III and then bypass this? Yeah. It's a great question, and just to be totally clear, we haven't guided on this at all. We need to see that phase I data. We need to have interactions with the FDA and other regulators to really confirm our path forward. But there's certainly opportunities to move extremely quickly based off of that phase I biomarker data. Our current baseline assumption is we'll do something Alpine-like, is the way we like saying it, where there's a very targeted open label phase II, which we can very quickly get proteinuria data in patients. You'll remember they had about six patients' worth of data at 36 weeks, which they released, then were acquired by Vertex. But more importantly, they used that to very quickly pivot into a phase III. So there's a baseline expedited plan there, but we do wanna see if there's ways to trigger something even more expedited, but we need to have more regulatory feedback on that. All right. In terms of overall, you know, the regulatory path forward is thirty-six weeks, based on, I guess, proteinuria, but you know, like I said, we know the link where you can actually decrease, let's say IgA to a certain degree, and you should have it should be reflected in proteinuria. Is there any possibility of having a 24-week time point for accelerated approval? You know, we, we'll talk to the FDA. When you look at the kinetics of the response following APRIL inhibition, you take about 3-6 months to get to peak IgA reductions, and proteinuria continues to decline over time beyond that. We saw with zigakibart, out through two years, you're getting kind of incremental further reductions in proteinuria over time. Our goal is to deliver that best top-line number relative to Sibeprenlimab and zigakibart to demonstrate that best-in-class clinical activity. So bringing the primary endpoint forward may hurt us in our ability to do that, so I don't think we'd likely try to pull that accelerated approval time point up beyond what it currently is. Okay. And so, just in terms of the market opportunity, you mentioned greater than $10 billion. You know, I've slowly, you know, watched estimates increase from companies, and I think, you know, when I look at it, and I just take the academic literature, it's about 112, is my calculation, in the U.S. alone. You know, but then you have Novartis, who came out and said 185 thousand in the U.S., and I think AstraZeneca put a paper out which suggested about 199-200 thousand patients. So, you know, what does your market research sort of suggest? Yeah, it's in that range. I think the number that we quote most often is actually stated by the FDA, which is around a hundred and seventy thousand. So right in between those estimates that you outlined. But we do think it's a sizable market, probably one of the bigger rare diseases out there. Did you say a hundred and seventy, is the FDA- Hundred. Yeah, 170. Well, it's actually 169, but I think that's a little too precise for- All right. Yeah, I mean, that suggests to me, you know, if you just take the annualized price of Tarpeio, I mean, that's a. It's not a small market. You know, and especially so, you know, I guess one of the other takeaways from the KDIGO guidelines is basically they're reducing what's considered high risk. You know, according to a paper that was published, I think, in 2023, you just see even if you're at 0.5 grams per day, those patients, you know, migrate downwards towards kidney failure. So, I just want to get your perspective, and this is speculation. You know, what do you think is gonna happen? So Sibe's gonna be likely approved in November, and then you are gonna have, Atacicept coming right behind it. Are those two drugs going to get a broad label, or is there gonna be precedence, let's say Filspari precedence, where it was 1.5 grams per day on accelerated approval? Yeah, probably the most likely thing on accelerated approval is the FDA will hold with precedent and say it's approved for patients at high risk of disease progression. But they're actually pretty loose and flexible about the language of how they define that. They say generally above one point five grams a day, and I think what we saw with the previous agents, like Filspari, there was some liberal interpretation of that with nephrologists and payers. So it will probably get uptake kind of beyond that. And then when they have their eGFR readout and get the full approval, that's when the label will fully expand, is our expectation. Okay, we have one minute, but, two questions, so maybe we'll take two minutes. Your two other pipeline assets, anything that you can disclose about them? You know, anything - are they de-risk, like, anti-APRIL, or are they also- Yeah, well, we're not disclosing for competitive reasons. Just we've noticed as soon as you name a target, a lot of competitors pop up from China or other regions, so we're staying a little bit tight-lipped about it. With 201, we will anticipate being in the clinic in the first half of next year, so it's not far behind JADE 101, which is nice. We have disclosed it is a B-cell-depleting agent. So it is something that can be used broadly across a number of different systemic autoimmune diseases, so we're, we're very excited about the potential for it. It does follow the same playbook as JADE 101, where there is an asset that's further out front that does have some aspect of clinical validation in several autoimmune indications. But we think through our protein engineering partners at Paragon, we can improve upon that, that profile to deliver a best in, in disease profile. Okay, last question. We're sitting here a year from now, and I ask you, you know, what were the key value-creating accomplishments for Jade? What would you like to say? Yeah, I think the next year, well, the first year of Jade has been absolutely amazing. We started the company in June of last year, so think about in twelve months, we've hired an amazing team. We have a really world-class team of IgAN developers. We've secured this pipeline of three assets, and we've secured funding that can get us through some meaningful milestones. I think if you project out to the next twelve months, it's gonna be equally transformational. We've gone from a preclinical to now a clinical company, and we'll be at a stage where with JADE 101, we'll anticipate having that first in human healthy volunteer data where we can see the biomarker data. We can see the dose and dose interval to see if we are actually delivering that eight-week-plus dosing profile, which is gonna be really meaningful to these patients. We'll be able to see the biomarker response to say, "Are we replicating that high dose of Sibeprenlimab to have that best in disease clinical activity?" And be in a position to start running with patient trials at speed. So that'll be really meaningful for 101. 201, we anticipate having that in the clinic as well, so we'll have almost like parallel lead programs that we're gonna be working on. With 201 has very broad potential, so a very exciting asset. And then 301 will be kind of moving towards the clinic in the first half of 2027. So really transformational in terms of going from a preclinical company to a company with meaningful data, and multiple clinical assets. All right, Tom, Andrew, thank you very much for taking the time and joining us at the Cantor Fitzgerald Global Healthcare Conference, and I'll look forward to seeing the updates. Always a pleasure, Pete. Thank you.