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Good morning, and welcome to the Jade Biosciences JADE301 Conference Call and Webcast. Please note that this call is being recorded and will be available for replay on jadebiosciences.com. [Operator Instructions]

Now I'd like to turn the call over to Tom Frohlich, Chief Executive Officer of Jade Biosciences. Please go ahead.

Thank you, and good morning, everyone. We're excited by the continued progress that Jade Biosciences is making across our pipeline and the strong operational momentum behind our lead programs as we work towards our mission to bring life-changing disease-modifying autoimmune therapies to patients. Today, we are pleased to provide a closer look at JADE301, the third program in our pipeline, which we recently unveiled.

Moving to Slide 2. I'd like to note that today's discussion will include forward-looking statements. These include statements about Jade's development plans, product candidates and our cash runway. Because such statements deal with future events and are subject to many risks and uncertainties, actual results may differ materially from those in the forward-looking statements.

For a full discussion of these risks and uncertainties, please review our filings with the U.S. Securities and Exchange Commission. Please also refer to our corporate website, jadebiosciences.com, for additional information and disclaimers.

On to Slide 3. Before we begin the discussion on JADE301, I want to provide a brief overview of our pipeline. Our lead program is JADE101, a selective APRIL inhibitor that is currently in Phase 2 development for the treatment of IgA nephropathy, or IgAN, a chronic autoimmune disease that leads to end-stage kidney disease for most patients.

JADE101 is an ultra-high affinity, half-life extended monoclonal antibody that has the potential for best-in-class efficacy and for convenient every 12-week maintenance dosing from a single subcutaneous injection.

Following our positive interim Phase 1 data readout earlier this year, we are more excited than ever about JADE101's profile to deliver value to patients and capture a significant share of the large IgAN commercial opportunity. We expect to report interim Phase 2 data for JADE101 in 2027 and anticipate initiation of our Phase 3 registrational trial of JADE101 in the first half of 2027, pending FDA alignment.

Next in our pipeline is JADE201, a half-life extended afucosylated monoclonal antibody targeting BAFF-R, the B-cell activating factor receptor. We recently initiated a first-in-human study evaluating JADE201 in patients with rheumatoid arthritis from which we anticipate interim data in 2027. That takes us to the focus of today's call, JADE301, our potentially best-in-class half-life extended anti-interferon beta monoclonal antibody in development for dermatomyositis.

On to Slide 4. Earlier today, we announced that new preclinical data for JADE301 is being presented at this year's European Academy of Dermatology and Venereology Congress, or EADV. Dermatomyositis, or DM is a rare chronic and debilitating autoimmune disease characterized by painful inflammatory skin disease and progressive muscle weakness. Despite recent advances in treatment, it is a large and underserved opportunity with approximately 50,000 patients in the United States alone.

As you'll hear today, interferon beta is a key upstream driver of DM and is a clinically validated therapeutic target with selective inhibition demonstrating meaningful benefit across both skin and muscle disease. JADE301 was designed to optimize this mechanism with a goal of combining high affinity binding, enhanced potency and YTE-mediated half-life extension to support infrequent subcutaneous dosing.

In preclinical studies, JADE301 demonstrated greater potency and an extended half-life in nonhuman primates versus a dazukibart comparator. Dazukibart is a first-generation interferon beta inhibitor currently in Phase 3 development for DM. We believe these results support JADE301's potential as a best-in-class anti-interferon beta therapy. We expect to initiate a Phase 1 healthy volunteer study in the fourth quarter of 2026 with initial data anticipated in the second half of 2027.

We have the privilege of being joined today by Dr. Rohit Aggarwal, a Professor of Medicine and the Medical Director of the Arthritis and Autoimmunity Center at the University of Pittsburgh, where he serves in the Division of Clinical Immunology and Rheumatology. As a treating physician and clinical investigator, Dr. Aggarwal will provide perspective on dermatomyositis, the patient and treatment burden, the evolving treatment paradigm and the biological rationale for targeting interferon beta.

Then Dr. Andrew King, Jade's President of R&D, will introduce JADE301's differentiated profile, walk through the preclinical data being presented at EADV and provide an overview of our development plans for the candidate.

But before I hand off the call to Dr. Aggarwal, allow me to first review the current and emerging DM treatment landscape on Slide 5, which underscores our conviction in JADE301's potential best-in-disease profile based on its mechanism and intended subcutaneous administration.

To orient you to the data in the table, efficacy in DM is measured primarily through 2 endpoints due to the skin and muscle disease manifestations of DM. TIS or total improvement score is primarily a measure of improvement in muscle weakness and injury. CDASI or Cutaneous Dermatomyositis Disease Area and Severity Index is primarily a measure of skin severity. In the table, week 12 results of each therapy and the furthest reported data are included to provide additional context.

Current standard of care in DM is quite burdensome for patients, relying heavily on steroids that can lead to significant side effects while leaving residual disease activity. Notably, when viewed through the lens of efficacy, safety and convenience, each of the agents currently approved or in development carries a meaningful trade-off. IVIG, although approved for this indication, requires multi-day IV infusions and carries thrombosis and renal risks.

Brepocitinib, which was recently approved, represents an important advance. However, as a TYK2 JAK inhibitor, it comes with a black box safety warning of serious infection risk, increases in mortality, malignancy, MACE and thrombosis. Additionally, we believe there is significant opportunity for further improvement in both skin and muscle outcomes.

Anifrolumab, which is dosed weekly subcu, blocks the IFNAR receptor, inhibiting the interferon pathway more broadly, including both interferon alpha and beta and potentially increasing the risk of viral infection and reactivation.

Efgartigimod, which is also dosed weekly subcu and in a 5 mL formulation works through FcRn antagonism and therefore, may not address the underlying interferon beta-driven biology implicated both in skin and muscle disease. Lastly, as you can see here, dazukibart, a selective interferon beta inhibitor, has shown robust muscle improvement and the strongest cutaneous benefit in the disease to date, which supports interferon beta as an upstream target.

However, dazukibart has low subcutaneous bioavailability and therefore, is delivered by IV infusion every 4 weeks. So when you look across the field, no therapy today combines the attributes that matter most, efficacy across both cutaneous and muscle components of the disease, a clean safety profile and convenient administration to minimize treatment burden. By pairing selective interferon beta neutralization with subcutaneous dosing, our aim for JADE301 is best-in-disease clinical activity with a well-tolerated profile and a convenient dosing regimen.

With that, I'll now turn the call over to Dr. Aggarwal to tell us more about dermatomyositis and the underlying biological rationale for selectively targeting interferon beta.

Thank you, Tom, and good morning, everyone. Turning to Slide 7. Dermatomyositis is a serious debilitating autoimmune disease that affects approximately 50,000 adults in U.S. It's a complex multisystem condition that is characterized by painful skin disease as well as progressive proximal muscle weakness that brings functional impairment. Unfortunately, up to 80% of patients do not achieve sustained remission in this disease area. Instead, they experience chronic painful disease with profound impact on their activities of daily living, underscoring the need for more effective treatment as well as better tolerated and durable treatment options.

The burden on the patient is profound. Muscle disease can impair basic activities of daily living such as walking, climbing, stairs, bending, lifting and so on, while painful skin disease and severe itch can disrupt their sleep and quality of life. DM or dermatomyositis can involve other organs, including lungs and cardiovascular system. The treatment goal for patients with dermatomyositis is to reduce skin as well as muscle disease activity, preserve strength and daily function and reduce the burden of chronic treatment.

Turning to Slide 8. As Tom outlined, approved therapies, including IVIG and more recently, brepocitinib have expanded treatment options for patients with dermatomyositis. But from a physician perspective, however, the treatment decisions still require balancing efficacy, safety, steroid burden as well as convenience. No single therapy is ideal for every patient and treatment often needs to be individualized based on disease manifestation, organ involvement as well as patient-specific factors. As a result, many of these patients continue to require corticosteroid and additional immunosuppressive drugs to manage their disease chronically.

Despite these advances, residual disease burden is substantial. Many patients continue to experience ongoing symptoms, disease flare and treatment-related burden, highlighting the need for additional therapeutic options for our patients. Ultimately, physicians would welcome therapies capable of delivering durable control of both skin and muscle disease while minimizing safety concern, steroid exposure as well as treatment burden.

Turning to Slide 9. One of the hallmark biological features of dermatomyositis is activation of type 1 interferon pathway in both skin and muscle tissue. Among the type 1 interferon, the evidence increasingly point towards interferon beta as the key driver of disease pathogenesis. As shown on the right side of the slide, interferon beta expression is markedly elevated in affected skin of dermatomyositis relative to healthy control and serum interferon beta, but not interferon alpha has been reported to correlate with severity of skin disease in dermatomyositis.

This is important because it suggests that not all interferon signaling contributes equally to the disease. Ideally, we would like to target the pathway, which is most responsible for disease activity while preserving as much as possible the normal immune function of other pathways. We also know that interferon beta sits upstream of many inflammatory pathway implicated in driving skin and muscle injury in dermatomyositis, making it particularly attractive target for intervention.

Taken together, selective neutralization of interferon beta offers the opportunity to interrupt a central driver of disease while preserving the remainder of interferon system, a distinction that may have implications both in efficacy and safety.

Turning to Slide 10. As Tom mentioned, dazukibart is a selective interferon beta monoclonal antibody currently being evaluated in Phase 3 trial for dermatomyositis. From a clinical perspective, our Phase 2 data generated considerable interest because they offered the first opportunity to determine whether selective inhibition of interferon beta could meaningfully impact disease activity in patients with dermatomyositis. In that study, patients treated with dazukibart demonstrated substantial improvement in cutaneous disease activity as measured by CDASI.

In fact, 82% of the patients treated achieved at least 40% reduction in CDASI and the magnitude of improvement was notably greater than placebo across the dose groups. You can see the resolution of skin disease shown in the images on this slide. Importantly, the benefit were not limited to skin. The study also showed improvement in TIS or total improvement score, including patients with more prominent muscle involvement, and the therapy was generally well tolerated.

As a clinician, we are always weighing efficacy against the realities of long-term treatment. While these data validate the interferon beta as a therapeutic target, the treatment burden remains an important consideration when patients require an ongoing IV therapy.

With that, I will turn it over to Dr. Andrew King, Jade's President of R&D, to discuss JADE301 and the approach Jade has taken to build on this validated biology.

Thank you, Dr. Aggarwal, for joining us today and providing the clinical perspective on DM and the potential of selectively targeting interferon beta, a clinically validated therapeutic target in DM.

Moving to Slide 12. The goal with JADE301 is to deliver the full disease-modifying benefit of interferon beta neutralization in DM with a convenient, infrequent subcutaneous dosing schedule. JADE301 is a novel, fully human neutralizing antibody identified through a de novo discovery campaign and was selected and engineered to deliver a differentiated best-in-class profile.

In preclinical studies, JADE301 selectively bound interferon beta with higher affinity and greater functional potency than existing therapies. JADE301 also incorporates clinically validated YTE Fc engineering with the goal of driving half-life extension and supporting an infrequent dosing interval. It was selected with molecular properties, predictive of high subcutaneous bioavailability to address a major limitation of first-generation agent, dazukibart, which has low subcutaneous bioavailability that requires high IV dosing to overcome. We believe the profile of JADE301 has the potential to deliver the full disease-modifying efficacy associated with selective interferon beta inhibition in DM with a dosing profile that may meaningfully reduce treatment burden for patients.

With that, let's turn to the preclinical data presented at the EADV conference beginning on Slide 13. To benchmark JADE301, we generated a dazukibart comparator from the publicly available antibody sequence and evaluated both molecules side by side in the same assays and under the same experimental conditions. Across these in vitro studies, we observed a consistent pattern. JADE301 demonstrated higher binding affinity, greater functional potency and more effective suppression of downstream interferon signaling.

On the left side of this slide, JADE301 demonstrated approximately 2.5-fold higher binding affinity for interferon beta compared to dazukibart with a KD of approximately 11 picomolar versus 28 picomolar. JADE301 was also highly selective for interferon beta with no detectable binding observed to any interferon alpha subtype or any other interferon family member protein.

The middle panel shows a cell-based assay measuring interferon beta induced STAT phosphorylation in a human immune cell line in which JADE301 demonstrated potent and complete inhibition of interferon beta signaling with an approximately 2.5-fold greater potency than dazukibart.

Finally, in DM disease-relevant human dermal fibroblast shown in the right panel, JADE301 potently and completely inhibited interferon beta induction of MX1, an interferon responsive gene and a hallmark of the type 1 interferon response observed in the skin and muscle of DM patients.

The IC50 of JADE301 was 11 picomolar compared to 91 picomolar for dazukibart, representing an approximately eightfold improvement in functional potency. These data demonstrate that JADE301 combines selective, high-affinity interferon beta binding with potent downstream interferon pathway inhibition across multiple experimental systems, supporting the potential of JADE301 to block the aberrant interferon beta signaling characteristic of DM pathogenesis.

The data on Slide 14 show a differentiated pharmacokinetic profile of JADE301 in nonhuman primates, which has the potential to enable more patient-friendly dosing. On the left side of the slide, following intravenous administration of a single 30 milligrams per kilogram dose of JADE301 in NHPs, the PK profile was characterized by slow linear clearance and an extended approximately 30-day half-life, threefold longer than the approximately 10-day half-life for dazukibart in nonhuman primates. This result provides further evidence that half-life extension has been successfully incorporated into the JADE301 molecule, supporting its ability to potentially provide prolonged systemic exposure and a best-in-class profile.

On the right-hand side of the slide, following subcutaneous administration at 30 milligrams per kilogram, JADE301 demonstrated favorable pharmacokinetic properties with rapid absorption and an apparent elimination phase consistent with that observed following IV dosing, supporting the use of the subcu route in both nonclinical toxicology studies and planned clinical development. Translational assessments further support the potential for high subcutaneous bioavailability of JADE301 in humans.

The effective half-life extension observed with JADE301 in nonhuman primates, along with the predicted favorable subcutaneous bioavailability supports the potential for a very differentiated dosing profile and reduced patient burden compared to dazukibart, which requires high IV doses administered by infusion every 4 weeks.

On Slide 15, we are highly encouraged by the promising preclinical profile of JADE301 and look forward to advancing it into the clinic. This Phase 1 first-in-human trial will be a placebo-controlled single ascending dose study in 24 healthy volunteers across 3 dose cohorts.

The objectives of the trial are to evaluate safety and tolerability of JADE301 and impacts on pharmacokinetics and immunogenicity across a range of exposures to support dose selection and future clinical development in dermatomyositis. We expect interim data from this trial in the second half of 2027.

With that, I'll now hand the call back to Tom.

Thanks, Andrew. Turning to Slide 16. In summary, we want to leave you with 3 key takeaways.

First, interferon beta is a clinically validated target in dermatomyositis, which represents a large and underserved opportunity despite recent therapeutic advances.

Second, the preclinical data demonstrate that JADE301 combines the potential for enhanced potency, a half-life extended PK profile and subcutaneous administration. Together, we believe these attributes support the potential for a differentiated product profile.

And third, we are moving quickly into the clinic with Phase 1 initiation expected in the fourth quarter of this year and interim data anticipated in the second half of 2027. With cash runway expected into the fourth quarter of 2028, Jade is well capitalized to pursue efficient and expeditious development of all 3 programs in our pipeline.

With that, I'll hand it back to the operator to open the line for questions.

[Operator Instructions] Our first question will be coming from the line of Alex Thompson of Stifel.

This is [ Patrick ] on for Alex. Thanks for the update here. I guess can you guys just walk us through maybe the path after the 2H '27 interim? I guess what do you need to see to go into DM patients? And is there a version of this readout that lets you maybe skip a small POC and go straight to a Phase 2b? Or is the POC certain here?

Yes. Thanks, [ Patrick ]. Really appreciate the question. Ed, do you want to talk a little bit about the development pathway after Phase 1?

Sure. Yes. So I think the Phase 1, as you point out, we want to understand the PK preliminary safety. I think at this point, probably a little too premature to comment on what the later stages of development look like. I think the other interesting piece will be the dazukibart Phase 3 readout. So I think that will help inform things as well.

Yes. Maybe just to add to that. Yes, out of the Phase 1, our goal really is to demonstrate that subcu profile. We think that's a huge advantage for patients over the IV administration of dazukibart. So that's going to be really the big win. We'll be able to then characterize what does the human half-life look like and make some dose predictions. The really nice thing, as Ed pointed out, is we'll learn a lot from dazukibart to really understand what are those C-trough concentrations that we need to hit to get that level of efficacy.

And so we'll be in a really good position to move the program forward quickly. So we'll provide more guidance as that program the data emerges.

And our next question will be coming from the line of Tyler Van Buren of TD Cowen.

Dr. Aggarwal, if you're still on, it would be great to hear what your patients complain about most when it comes to symptoms when they present in the clinic. What symptoms are most bothersome. Obviously, you listed a bunch of them, but it would be great to hear which ones they talk about the most.

And then for the Jade team, again, maybe you could just on the Phase 1 data at the end of next year, maybe you could elaborate on some of the biomarkers that you'll be able to show in this early study that could be reflective of efficacy and how we could compare that to the dazukibart data?

And also maybe talk a little bit about the distribution into the muscle tissue and how meaningful that could be?

Thanks so much, Tyler. Yes, Dr. Aggarwal, why don't you talk a little bit about and then we can hand it over to Andrew to talk about the expectations around the Phase 1 data.

Sure. So basically, each patient is very different. So there are different constellation of symptoms that everybody would report. But [ Tyler ] mostly, patients would report difficulties in activities of daily living. The things that you and me take for granted and we don't even think about for a second, getting up from a chair is incredibly difficult for our patients. They need help. They need to push through. Going up the stairs, sometimes it's impossible for my patients. They have to change their -- where they're living because they just can't go up the stairs.

So things getting in and out of car, getting up from a toilet seat, all of those activities, lifting a gallon of milk that we think are -- we don't even think is difficult for our patients. That's one thing they complain.

The second thing they complain if they are rashes is not the cosmetic part of the rash. It's the painful quality of life altering part of the rash. It's painful burning, itchy, that really drives them crazy, not so much the cosmetic part.

And the third most debilitating symptom that I hear is the lungs where they have shortness of breath or cough and when they -- as you know, many of myositis patients would have ILD. So those are the 3 main most common manifestation, but it also depends what the patients currently have. Some patients may have more skin, some may have more muscle, some may have a mix of all. So every patient is a different story. So maybe over to Andrew.

Yes. Thanks for the question, Tyler. The Phase 1 study will primarily be focused on pharmacokinetics for guidance on the dosing strategy moving forward. Unfortunately, interferon beta is negligible in its expression in healthy volunteers. So there's no direct way to get pharmacodynamic target engagement measurements to help guide that dose selection. We will incorporate some exploratory ex vivo type PD assessments as a guide, but our primary dosing strategy is around matching the C-trough of dazukibart with a more potent molecule.

As we highlighted, the binding affinity is approximately 2.5-fold higher with JADE301 relative to dazu and the functional potency up to 8x higher than dazukibart. So being able to match those C-troughs of dazu with a more potent molecule gives us high confidence. We'll deliver the full disease-modifying benefit of interferon beta neutralization One of the key considerations, as you mentioned in your question, is antibodies distribute at relatively low levels to the muscle, the important target organ of injury leading to the muscle weakness.

Dr. Aggarwal described, only about 1% of the systemic circulating concentration of monoclonal antibody does achieve localization within the muscle tissue itself. So this requires relatively high C-troughs then to target sufficient drug concentration in the skeletal muscle to provide that impact. So that's going to be an important part of the translational modeling and targeting a C-trough that provides IC99s over interferon beta in the muscle and skin.

And our next question will be coming from the line of Akash Tewari of Jefferies.

So just thinking about Pfizer's trial design and their development path and really what you could do differently, right? I feel like some of the art on these dermatomyositis trials is what do you do on imputation? Do you decide to do steroid tapering in Phase 2 or not?

And I think one of the unique things about the Pfizer development plan is they kind of split out muscle and skin affected patients, but they really didn't have that many patients with muscle weakness. So when you think about Pfizer's trial design relative to what you would want to do, what are some clear changes that you think you would make in order to generate more meaningful data earlier or make a better clinical decision going into Phase 3?

Thanks, Akash. Yes, really good question. Yes, we've been looking at that Pfizer design quite closely. So I'll pass it to Ed. But just before I do, yes, we think that there are some very key learnings from that Pfizer trial. First of all, it's been a little slower to enroll, we think probably because it's IV, so that's probably not as easy.

And then also, they are including both DM and PM patients, polymyositis, which we understand has really added a lot of complexity to the trial in terms of recruitment. So we think going into a pure DM population will really help just enhance that enrollment. Ed, do you want to talk a little bit about how we're thinking about patient selection?

Yes, sure. So -- and again, I would just reiterate what Tom said. First and foremost, we will we will not be doing a basket study or we're not envisioning doing a basket study. We will only be enrolling patients with DM. I think the lesson that we learned from the Pfizer Phase 2 is exactly what you pointed out. They had a much more significant population of skin only with a higher CDASI requirement, and they had fewer on the muscle side, I think only 18. We know that in DM, it's about 20% to 30% of patients have skin-only manifestation.

So our view in terms of the inclusion criteria would be to ensure that patients have both active skin and muscle disease and then potentially study subpopulations where they have more skin exclusively active disease. In terms of the inclusion/exclusion criteria, I think similar to what you've seen across the brepocitinib studies, I think that's very representative inclusion/ exclusion. We'll use that as a guide going forward.

And just to follow up on that. In terms of incorporating steroid tapering in Phase 2, would that -- so it sounds like, yes, you will have steroid tapering in Phase 2?

So I mean we -- it's probably a little bit early just to talk about the exact trial design. But obviously, that's been a big advantage with what we've seen with brepocitinib and then as well with efgartigimod. So that's definitely something we'll look closely at.

And our next question will be coming from the line of Laura Chico of Wedbush.

Just a couple of housekeeping questions. First, apologies if I missed it. But on the Phase 1 study design, have you disclosed the dose amount that you're going to be evaluating for the subcu?

Number two, what do you know about immunogenicity so far in the nonhuman primates? And will that be one other assessment you'll be sharing after the Phase 1?

And then one for Dr. Aggarwal. Just out of curiosity with a couple of different mechanisms advancing, how do you envision physicians making selection choices on which therapies to use in patients?

Great. Thanks, Laura. Maybe just really quickly on the first question. No, we haven't disclosed the doses at this point. And then maybe I'll turn it over to Andrew to talk about the immunogenicity question. And then Dr. Aggarwal, if you could talk about how you select which class of agents for which patients.

Yes. Thanks, Laura. So the immunogenicity profile in nonhuman primates has been fairly benign, although not especially predictive or translational to humans. By design, JADE301 is a fully human monoclonal antibody that was discovered in a de novo antibody discovery campaign in humanized mice. So that provides the greatest potential mitigation of immunogenicity by being fully human by design. We will be measuring ADA rates and the impact on PK in the healthy volunteer study, but by design, have attempted to reduce the risk of immunogenicity for the program.

Thanks, Andrew. And Dr. Aggarwal, can you just comment on?

Yes, I can speak to it. So basically, the concept that what your question is raiser rather than which one I would prescribe first is a more appropriate question because I do believe that almost all of these drugs that are in development will get used in the life of a patient of a dermatomyositis because it's a chronic disease.

And we have -- just to give you an example, rheumatoid arthritis has 21 drugs approved. It's only the fight is which one I would use first. But if I look at the history of my patients over 10 years, 20 years or chronic inflammatory autoimmune conditions, almost in most of my patients, I've used a bunch of them, 6, 7, 8 agents have been used over the life because what happens is that one agent would work and then may eventually stop working or the body breaks through that and then they may get a flare and the next agent may be used.

So I think more appropriate question, honestly, is which one I would use first and which of these mechanism of action I would use first. It also depends on -- and specifically in dermatomyositis, we probably have 2 main mechanisms right now, but they are all both the JAK/TYK pathway, IVIG and interferon pathway. JAK/TYK pathway and interferon pathway are pretty much the same pathway. So simpler drugs such as oral would be preferred as a first agent over subcu and subcu would be preferred over IV in the same mechanism of action.

But when you talk about in a particular patient, it also depends on the risk profile of the patient. Let's say the patient has severe cardiovascular risk, then maybe one drug would be preferred over other. Patient may have pregnancy, then one drug IVIG may be preferred over others. So there are many nuances when you talk about individual patient, which drug I would prefer first.

But what I do believe in each disease state of myositis, such as dermatomyositis, we need multiple mechanism of action and multiple different drugs to really take care of the patient for the whole lifespan of the patient, which spans about 30, 40 years.

Come from the line of Michael Yee of UBS.

A couple of questions from our side. What do you know or what has been published or what do we know about dazu's PK/PD profile from the standpoint of saturating or recovering the target such that your drug, which is more potent and may require less drug will have room or opportunity to be higher efficacy than what Pfizer is doing in an IV formulation and probably giving a lot of drug. That's question one.

Question two is, to what extent could you seek or look at other indications given the profile of your drug and given the opportunity to go elsewhere and have a broader development plan, would that be something that could be interesting in Phase 2 beyond just DM?

And then last question is, given that Pfizer has taken a long time to enroll their study, and I note that there's changes on ct.gov for completion. Is there anything that you think we would learn from them or from others that would help further derisk your program?

Great. Thanks, Mike. Really appreciate that. Andrew, do you want to take that first question on the dazu PK/PD? And then actually, maybe you can take the third one as well, which is the -- what will we learn from dazukibart that we can apply. And then I'm happy to talk about indications.

Yes. We have looked at all the publicly available PK/PD modeling, including from the patents from dazukibart Unfortunately, it's not a particularly biomarker-rich disease state. As I mentioned previously, there's low levels of circulating interferon beta that's difficult to get direct assessments of target engagement. Based on translational modeling, that 600-milligram dose does appear to be covering the IC99 in muscle, so providing a robust inhibition of interferon beta. It is very important to have very tight interferon beta control because it's upstream in an amplification loop that drives further interferon beta production and tissue injury.

With JADE301, our goal is to match the C-trough of dazukibart with, as you mentioned, a more potent inhibitor and with the half-life extension incorporated and the potential for prolonged smooth systemic exposures, if there is additional efficacy left on the table, we feel like we're in a great position to capture that.

Although a very differentiated dosing profile from dazukibart shifting from IV monthly dosing to subcu infrequent dosing, we think in itself represents a very significant differentiation, a reduction in patient burden and an important innovation relative to dazukibart. So that's the first question. Can you repeat the third question again, sorry?

Yes. The second question was around thinking about your mechanism or whether you could look at other indications beyond DM that could differentiate the profile of the drug and go broader than just DM given the landscape.

I just recall, you did ask about learning from the dazukibart clinical experience when we expect to see more information. We actually just saw a recent publication from the [indiscernible] and no new safety signals. So consistent with the initial clinical experience of a safe and well-tolerated mechanism. The next major learning will come from the Phase 3 trial that's currently ongoing. It's on clinicaltrials.gov to have a primary completion date in the middle of 2027.

So that will provide significant further derisking of the interferon beta mechanism in dermatomyositis and also provide some potential in polymyositis, which also is being enrolled in that trial. And that could be an important guide for potential life cycle management or indication expansion. But I'll turn it back to Tom to continue on the broader potential of JADE301 in outside of DM.

Thanks, Andrew. And your line is breaking up a little bit. So maybe I'll just quickly repeat the dazukibart Phase 3 data. I think the primary completion date is listed as July 2027. So that's when we'll learn a lot more about the results of that drug, which will help guide our development strategy. Yes, in terms of indications, as Andrew mentioned, they're also looking at polymyositis. So we'll look closely at that data, understand what's the pathway there.

But there are other indications as well that we're considering things like cutaneous lupus and there's some other interferon beta-driven diseases that we want to evaluate, but really believe there's a large opportunity with dermatomyositis. We know there's 50,000 patients in the U.S. alone.

And also recently, with brepocitinib being approved, we saw that they priced at $420,000 a year. So I think that's a very large and substantial commercial opportunity. With Jade's differentiated profile, we can capture a large portion of that opportunity. So we feel really excited by that. Thanks, Mike.

And our next question will be coming from the line of Julian Harrison of BTIG.

I have a related question on the topic of potentially best-in-class efficacy. I just noticed that positive dose response in the dazukibart Phase 2 results. I'm wondering how supportive is that observation in the potential of JADE301 having a best-in-class efficacy profile in addition to dosing. It sounds like you likely have a preferential drug at parity efficacy, but would love to get your thoughts on that upside scenario.

And then I understand polymyositis is a little more heterogeneous than DM, but I wanted to know if you see any optionality there for the interferon beta class? And if so, what would that TAM expansion likely look like? And what do you maybe have to see from dazukibart's Phase 3 to get more supportive of that opportunity?

Yes. Thanks, Julian. Yes, on the dazukibart efficacy, we feel really encouraged by the Phase 2 data. We saw that highest level of activity on CDASI, so on the cutaneous component. So I really feel like that's going to be a big driver of uptake for the interferon beta class and also very positive response on the total improvement score, which is a good barometer of the neuromuscular efficacy.

So I do feel like that efficacy is very substantial with interferon beta. However, the study was small, so we'll have to look at really what the Phase 3 looks like. And it's hard to say at this point really if we can improve upon that just because that Phase 2 study was fairly small. We need to look at what's occurring in the Phase 3. We're really encouraged by Jade's profile with 2.5-fold greater potency and binding affinity. So feel like we do have a good opportunity to capture any efficacy that is available.

In terms of PM, yes, we'll look really closely at that data from dazukibart. And if it's offering benefit to patients in terms of disease activity with the safety profile that we anticipate, and that's definitely something that we would consider because having the differentiated subcu dosing with JADE301 over dazukibart, we think will be a really big advantage and really enable patients to get that efficacy without the treatment burden. So we'll look at that very closely. Thanks, Julian.

And our next question will be coming from the line of Rami Katkhuda of LifeSci Capital.

I guess how heterogeneous is interferon beta activity across DM patients? And could baseline interferon signatures or, I don't know, other biomarkers influence efficacy with the mechanism?

And then secondly, do you have a sense for the level of target coverage required in skin versus muscle? And could those compartments ultimately drive different dose requirements with this mechanism?

Thanks, Rami. Yes, those, I think, are great questions for Andrew. Do you want to look at interferon beta heterogeneity across patients and then also differentials in muscle and skin?

I'm not hearing from Andrew. So Ed, do you want to take that question?

Yes, sure. So I mean, I think with regards to the heterogeneity, as was alluded to earlier, I think one of the things that we're aware of, particularly when it comes to monoclonal antibodies is their penetration of the muscle tissue is going to be significantly less, maybe anywhere in the range of 1% to 4% of what you see systemically.

Pfizer in their Phase 2 did skin biopsies, and they did look at the gene signature of interferon beta and showed a substantial reduction after treatment that was correlated with clinical response. I'm not aware of a significant amount of muscle biopsy data. They didn't conduct muscle biopsies, and it's not standardly done at this point in the disease. So I can't speak on the relative level of activity there. But it is in preclinical models has been evaluated as being a very high interferon beta disease.

So I think the expectation is that you're probably having at least similar activity in the muscle as compared to the skin. It's really more of by targeting that C-trough, making sure that we're getting a gradient that allows the monoclonal antibody to penetrate sufficiently to silence the local interferon beta activity.

And our next question will be coming from the line of Matthew Phipps of William Blair.

Should the base case assumption be that a 12-week subcu can be achieved given the 3x longer half-life? Or with Pfizer, given 600 mg IV, should we assume that to maintain that kind of C-trough with a dose that fits in an auto-injector subcu, it might need to be a little more frequently? Just curious what kind of base case assumptions you have going into this trial?

Yes. Thanks, Matt. Appreciate the question. We think the goal here is just really getting to subcu dosing over dazukibart will be really the largest differentiator in terms of patient convenience. So that's really the primary goal we're trying to establish through the Phase 1. We will have to look at what is the human half-life exposure levels, the subcutaneous bioavailability in the Phase 1 to really be able to be more confident in terms of what that dose interval is.

We do feel like with our profile, as you mentioned, more potent and longer half-life that at least we'll get to that Q4-week dosing that dazukibart has subcu, but potentially a little bit longer. But it's probably a little bit premature to really guide on what we anticipate the full dosing schedule to be. The really nice element here, though, is we do know what the C-trough levels are for dazukibart.

So we'll really be able to triangulate from the dazukibart C-trough levels to what we're seeing in our human exposure and half-life to be able to really have a very good characterization of what that dose and dose interval will be for studies going forward after the Phase 1. So hopefully, to be able to move extremely quickly from that point forward.

And just a quick follow-up. Dazukibart in the Phase 2, it was nonsignificant increase in [ MMT-8 ]. Is that just a function of the small trial because it did show improvements in creatinine kinase. Just curious how you think about the specific muscle benefit.

Yes. Ed, you've looked really closely at the dazukibart trial. Can you comment on [ MMT-8 ] and creatinine?

Yes. I mean the trend was very positive. Our assumption is that it is due to small numbers. That's why we're really excited about reading out with a larger Phase 3 treatment and middle of this coming year.

So I think looking at [ MMT-8 ], the -- as I said, the trend was very strong. So I expect it to be statistically significant with a larger treatment population.

And our next question will be coming from the line of Arthur He of H.C. Wainwright.

So I have 2 questions. One for the Jade team. When I look at the poster, you guys evaluated the drug impact from the MX1 expression. Just curious, have you guys looking at that in the primary cell from the DM patient?

And the second question is for Dr. Aggarwal. If we only look at the DM patients, is that possible we just rely on the CDASI as the primary endpoint? Or we still need the [ TIS ] for the -- including for the primary endpoint?

Thanks, Arthur. Great to hear from you. Andrew, are you back on the line? Are you able to address -- did you hear the question about MX1 and primary cells?

So at this time, we've only measured MX1 in normal human dermal fibroblast as well as PBMCs from humans as well as nonhuman primates. MX1 is a downstream target during of the interferon beta pathway and is a hallmark being upregulated both in the skin and the muscle in DM patients.

However, at this time, we haven't directly assessed the impact of JADE301 in the setting of DM in those cell types. But it's a great question and something we're beginning to explore as to how to continue to build out translational confidence in the interferon beta inhibition pathway in the setting of clinical DM.

Thanks, Andrew. And Dr. Aggarwal, do you want to comment on kind of use of versus [indiscernible]?

Right. I can -- so even mainly that we have to ask what are the regulators saying. So regulators so far, FDA has been very clear that they see dermatomyositis as a multisystem rheumatic disease, not a skin manifestation, not a skin disease.

So basically, CDASI would be great to have as a proof of concept as a subsecondary outcomes as well as the supportive evidence. But I think they would -- any study would have to demonstrate overall improvement with TIS as a primary endpoint. I don't think CDASI would be the primary endpoint in any of the ongoing trial unless FDA changes their mind, mainly because CDASI speaks only to the skin, whereas TIS speaks to muscle, but also include other organs, and that's the comprehensive nature is what the FDA is really looking for. Did the disease overall get better, not only about the skin.

Thanks, Dr. Aggarwal. And just to build on that a little bit as well, we do know that patients complain quite a bit, as Dr. Aggarwal pointed out, about the pain associated with the skin manifestations. We know there's trouble sleeping in the majority of patients. We know actually 50% of patients are on opioids for their skin pain.

And so we do believe that, that impact on CDASI, which we haven't seen dramatic improvements with the current standard of care or some of the emerging therapies in development. That's where we think interferon beta can really differentiate substantially. So not only on better TIS improvements on that neuromuscular and other organ systems, but particularly around that CDASI and skin improvement.

And our next question will come from the line of Kaveri Pohlman of Clear Street.

This is [ Wayne ] on for Kaveri. So how much early biomarker data will be needed to determine whether JADE301's higher affinity can translate into superior efficacy versus similar drugs? And will the Phase 1 SAD, MAD studies provide sufficient clarity? Or will a Phase 2 data, will that be needed to establish the superiority?

And then you mentioned the current cash runway is into 4Q '28. So how much development does the current cash position support? And are you considering partnering the asset after generating the POC data?

Thanks. Maybe I'll take the second question first, [ Wayne ], and thanks for the questions on cash runway. And then hand it over to Andrew to talk about how we're thinking about the data of Phase 1 to guide development. Yes, the current cash runway does get all 3 of our programs through into 2024 into -- sorry, into 4Q '28 across JADE101.

So readout of the Phase 2 trial in 2027 as well as initiating that Phase 3 trial, continued development on JADE201. And then with JADE301, it is funding the Phase 1 trial fully through the milestone of the data in '27 and then initiating a subsequent trial after that as well. So really, we feel like we're well financed through multiple catalysts and inflection points that will really create a lot of value for the company.

Andrew, do you want to talk about the biomarker in Phase 1 and how that's guiding our development?

Yes. Thanks, Tom. The primary focus in Phase 1 will really be on the pharmacokinetics of JADE301 and matching the C-trough of dazukibart, which has provided that strong clinical efficacy in Phase 2 and the dose they've moved forward with in Phase 3. Interferon beta expression in healthy volunteers is very low.

So it's difficult to get a direct assessment of target engagement to understand the functional potency of JADE301 in that early phase study. However, we are trying to incorporate exploratory pharmacodynamic biomarker assessments that may provide some initial hint in the clinical setting of that improved potency relative to dazukibart. But ultimately, we're going to need to see patient data in DM, both on the cutaneous and muscle manifestations to have a better picture of the comparative efficacy profile relative to dazukibart.

And our next question will be coming from Arseniy Shabashvili of Guggenheim Securities.

This is Arseniy on for [ Vamil ]. I think you just alluded to this, but what would be the next step after this planned Phase 1? Would it be a MAD study in healthy volunteers? Or would you be going straight into patients?

Thanks, Arseniy. Andrew, do you want to take that one?

Yes. We would expect the single ascending dose study in healthy volunteers to then set up and support future studies in DM patients. We have no plans to do a multiple ascending dose study in healthy volunteers. What we need to do is really align with regulators on the future development.

This is a rare disease, and there could be approaches to develop JADE301 very efficiently in this indication. But what the Phase 2 and subsequent Phase 3 look like, it's a little premature to guide on that prior to interactions with regulators to understand expectations. But our goal is to advance the program as quickly as possible into DM patients as the next phase of development for JADE301.

That concludes the question-and-answer period. I'll now turn the call back to CEO, Tom Frohlich, for closing remarks.

Great. Thank you, operator. On behalf of the Jade Biosciences team, thank you for joining us today. A replay of this webcast will be available on our website. If you have further questions, feel free to reach out to our Investor Relations team at [email protected]. Thank you.

And this concludes today's conference call. All parties may now disconnect.

I am Citi's U.S. health care strategist -- filling in this morning, but I'm very glad to have the team of Jade Bio here with us. And from the company, we have Tom Frohlich, CEO; Ed Conner, Chief Medical Officer; and Andrew King, who runs R&D. So we'll go about 30, 35 minutes and then. Okay. There we go.

All right. So we'll go about 30, 35 minutes. And if there are any questions at the end, feel free to certainly fire away.

So maybe, Tom, maybe start right at the top. For anyone in the room or listening who doesn't know Jade Bio well yet, how about a quick overview, what is the company and what are you guys building?

Yes, happy to. And first of all, thanks, Trevor, for hosting us and the entire Citigroup. We're excited to be here. Yes, so Jade Biosciences, we're a company focused on developing best-in-class therapeutics for autoimmune disease. We have 3 assets in our pipeline, all of which we've sourced from Paragon, which is a really high-quality protein engineering company based out of Boston with a long track record of developing really high-quality antibodies that have half-life extension to really deliver kind of the maximum efficacy available to any given target with a really long duration of action that really minimizes treatment burden for patients.

Our lead asset is JADE101. It's an anti-APRIL monoclonal antibody targeting IgA nephropathy as the lead indication. We think IgA nephropathy is an area of large unmet need and potentially a very large market size, about a $20 billion opportunity in the U.S. alone. And we're completely convinced that the anti-APRIL class is going to become the dominant class within IgAN really becoming foundational therapy for patients because it really does have the ability to have deep reductions in IgA, which is the pathogenic driver of the disease. It has deep reductions of proteinuria and can stabilize kidney function as measured by eGFR with very good tolerability. JADE101 has a very straight line of becoming the best-in-class anti-APRIL. We've recently reported some Phase I data showing that in healthy volunteers, you get very large reductions in IgA, actually nearing 70%, which is the largest reductions seen to date with any agent.

So we believe that, that will drive really meaningful proteinuria reductions for patients and then lead to stabilization of eGFR. Also in that data, we showed that, that reduction in IgA can be sustained for 12 weeks. which we think will be extremely convenient for patients and minimize their treatment burden over time. So that program is very exciting for us. We're advancing it. It's currently in a Phase II trial with that data reading out next year in 2027. But we aren't waiting for that data to initiate a Phase III. That data is not gating. We're very convinced by the characterization of the profile from that Phase I data to enable us to activate that Phase III. So we are aiming to get that trial initiated with the first patient dosed in the first half of 2027.

So a very rapid pathway to getting to market with JADE101. The second program we have is JADE201, which is an anti-BAFF receptor antibody, really following the footsteps of ianalumab, which is a product targeting the same target at Novartis currently in 6 different Phase IIIs across a number of different autoimmune diseases. And that's a B-cell depleting drug. so has really activity or the potential for activity in any indication where rituximab is standard of care. That's -- so it has very broad utility. We currently are in a Phase I rheumatoid arthritis trial with that medication. We'll be reading out that data in 2027 to really give us a characterization of that product. But what's interesting there is ianalumab, what we're doing is we're solving the limitation that it has.

It has a very short human half-life, just 10 days in humans. So with JADE201, we're aiming to extend that half-life, which would allow us to be able to have more complete coverage of the receptor for the duration of the dosing interval and then, of course, extend out that dosing interval as well to make a more convenient product for patients as well. So that program will read out the data in 2027. On JADE301, our newly disclosed program, that's an anti-interferon beta targeting dermatomyositis, a very severe disease that has muscle weakness, muscle degradation and then as well as painful and itchy skin lesions. Current treatment is very burdensome.

It's treated by steroids and IVIg -- which is very difficult for patients. There is an interesting pipeline coming along for brepocitinib. The JAK1/TYK2 was just recently approved by Roivant. So really demonstrating the unmet need there and they have very favorable pricing there. But we believe we can deliver a better profile with interferon beta. There is a more advanced asset with Pfizer right now that showed very compelling Phase II data with interferon beta in dermatomyositis with a very robust improvement in TIS. That's the primary endpoint. But very importantly, also very good efficacy on the skin component of dermatomyositis, which historically with other medications has been very difficult to treat.

So we're going -- going to improve upon dazukibart, which is the Pfizer interferon beta product. It has a very low bioavailability, so it needs to be delivered IV. And we believe with our protein engineering that we can overcome that and deliver a much more convenient format for patients. So that program is scheduled to enter into the clinic in Q4 of this year with a readout in 2027 as well. So a big year coming up. That's all underpinned with a very strong team and as well, we're significantly financed. We closed the last quarter with $461 million, which will fund us through all of those programs through into Q4 2028. So a very exciting time for us with the big year coming up in 2027.

Great. Yes. Thanks for that very extensive overview. So I guess I'll start with a competitive question just because it's -- I would say it's the sort of the freshest thing on the taste. So you had an earlier-stage competitor out last week with some Phase I data for their long-acting anti-APRIL drug. And the regimen that they're taking forward is -- seems to be landing in a pretty similar place to yours on dosing interval. So how do you read that data set? And does it change how you think about where JADE101 sits in the class?

Yes. So we obviously looked at that data in detail and remain really excited about the best-in-class profile of JADE101. When we started out with the selection of a best-in-class anti-APRIL, we really focused on 2 properties that needed to be optimized relative to the first generation. One was half-life extension to be able to extend the dosing interval. IgAN is a disease that's diagnosed in 20- and 30-year-olds, and they require lifelong therapy. So reducing the patient burden and giving them freedom from their disease with a disease-modifying mechanism of action, we think represents a significant value for those patients.

The second property where we saw limitations of the first-gen agents was on potency. And there's a large amount of APRIL within the body that needs to be neutralized to drive rapid and deep and sustained IgA reductions. And the first-generation agents had relatively modest potency. JADE101 was selected with ultra-high binding affinity to APRIL. It's actually a femtomolar inhibitor to APRIL with a Kd about 750-fold lower than sibeprenlimab, the drug approved by Otsuka and about 2,000-fold higher than Climb Bio.. So when we review the new data set from CLM, they look to have effectively half-life extended the agent similar to JADE101. But where we see the big advantage for JADE101 is the superior potency, resulting in faster, deeper and more consistent IgA reductions that we think has the ability to deliver the best-in-class efficacy, the full efficacy available to B-cell modulation with a convenient infrequent quarterly dosing profile.

So strong competitor from CLMb, but we still really comfortable with the properties and profile of JADE101 and are excited to really focus on rapid development and advancement of that program.

Great. So you had mentioned the Phase I interim results and you presented those back in June. So maybe just take us back before that readout, what were you hoping to achieve with the data? And how did you sort of -- and how does the data that you eventually generated actually compare to that coming in?

Yes. So healthy volunteer data in IgAN, as you know, is very significant because you can measure IgA levels in healthy volunteers, and that's a direct read-through to what you anticipate seeing in patients, and it's a predictor of clinical activity. So it's really derisking for the program on the whole, as I mentioned in the intro and allows us to move really quickly. So going into that, we wanted to have kind of comparable IgA reductions as was seen with the first generation of anti-APRIL therapies, which all of which achieved around 50% to 55% reductions in IgA with a single dose.

And then the other thing we want to do is have extended dosing on that. What we've managed to achieve was nearly a 70% reduction in IgA, which is unprecedented and really hasn't been seen with any other agent with a single dose to date. And that was lasted for up to 12 weeks, which really does support that idea that we can have Q12-week dosing interval. So it was really exciting data for us, really derisked the program, showed that we did achieve that best-in-class profile that Andrew described and gives us confidence to move forward really, really quickly.

Great. And on the biomarkers, so historically, how well have they sort of carried across from healthy volunteers into actual patient studies?

Yes. It's really exciting that the IgA reductions observed in healthy volunteers have been highly consistent with those observed in IgAN patients. So it really does set up our program to move forward quickly in clinical development. What we've seen is that these early IgA reductions, whether they're in healthy volunteers or IgAN patients as early as 8 weeks are highly predictive of the proteinuria reductions you see at week 36, which has typically been the primary endpoint of Phase III IgAN trials to support accelerated approval. So we do feel this data set is highly derisking in terms of translating to that disease-modifying clinical benefit we've seen consistently with the anti-APRIL MOA and allows us to have confidence in our dose and dose interval selection to move the program forward as quickly as possible into pivotal trials.

And what's the feedback from nephrologists that has sort of most shaped how you're developing JADE101? And is there something in there that you think maybe investors or even some of your competitors in the space are underappreciating at this point?

Yes. So I think the ultimate goal for nephrologists and patients is to stabilize kidney function for a long time. And these patients are typically diagnosed in their second or third decade of life. So they really do need lifelong treatment. And if someone is diagnosed, let's say, at the age of 25, they have a 10 to 12 year -- a 50% chance of losing their kidney functions over 10 to 12 years. So this is something that's chronic that will need to be really administered for the entire life of the patient. And so that really long-term view is kind of resonating and coming back to us a lot.

And so from that aspect, obviously, convenience is going to be a big driver because if you're a young patient, maybe in your work, maybe you're starting a family, you're really going to want to not think about your disease as much as possible. And actually, this disease is largely asymptomatic. So that convenience is really going to be important to make sure that the patients are staying compliant, but also managing their disease. So that's kind of one element that's maybe a little bit underappreciated. The convenience is going to be a big choice driver for clinicians. The second one as well is we're seeing with the more advanced agents, the first generation of anti-APRILs that we're seeing good eGFR stabilization in the clinical trials over a 1- or a 2-year period.

This is really, really encouraging because patients typically lose 5 to 6 mls per minute of eGFR function per year. and then stabilizing that back to kind of a normal kidney function is actually groundbreaking. And the data was actually presented recently at a conference and the nephrologists got up and applauded because they haven't seen anything like this before. So -- but a lot of investors come back to us and say, well, you can't do better than stabilization, which I think is a fair comment because we don't aim to do better than stabilization. But I think what people underappreciated is it's over a short period of time. It's only 1 or 2 years that these agents are stabilizing in the studies. But patients need to think about 30, 40 years out. And the best predictor of that long-term stabilization of kidney function is actually getting to very low levels of proteinuria.

In fact, all the longitudinal studies say, you need to get patients below 0.5 grams a day of proteinuria to really minimize that long-term risk of disease progression. So what we think is going to emerge in the differentiation of these products is not only having a good profile, but getting more patients down to below that target range of 0.5 grams a day, and that will be a key differentiator because that's what nephrologists are worried about for the long term for their patients. And that's actually a big driver why the KDIGO guidelines just recently changed to say the target for all patients is to get them below that 0.5 grams a day and in fact, down to below 0.3 grams a day, which is back into that clinical remission range. And so we think coming out with JADE101 that has the most potent reduction in IgA and potentially has the ability to get more patients into that range will be a big differentiator.

Great. And you mentioned eGFR. So I guess maybe diving a little deeper into that. Going after both BAFF and APRIL versus targeting just APRIL on its own, like what do we know about the effect on that particular endpoint from the dual mechanism versus single mechanism?

Yes. We've had a long-held conviction that selective APRIL inhibition is really the disease-modifying mechanism in IgAN because IgAN is a plasma cell-mediated disease, which is uniquely APRIL responsive and it provides a targeted and least immunosuppressive approach to IgAN patients. What was seen in eGFR, only one Phase III has read out, and that was the sibeprenlimab trial that Tom referenced earlier, showing stabilization of eGFR with a selective APRIL inhibitor over a 2-year period relative to the inevitable decline of about 10 mls over that 2-year period in the placebo group. EGFR was actually numerically above baseline at the end of that 2-year study in that patient population. So a really remarkable treatment benefit.

So the best pivotal trial evidence to suggest that selective APRIL inhibition alone is sufficient to provide that full eGFR stabilization benefit, which is the best we can hope for in IgAN because the loss of kidney function really represents loss of nephrons, which won't be regenerated with a therapy like this. In the Phase II studies, we have seen consistent stabilization of eGFR for various periods of time across selective APRIL inhibitors as well as dual APRIL/BAFF inhibitors. Zigakibart from Novartis has open-label Phase II data out through 2.5 years, which looks remarkably similar to that of sibeprenlimab in Phase III, full eGFR stabilization numerically above baseline out through that 2.5-year period in a high-risk IgAN patient population.

We've also seen open-label data from atacicept, a dual APRIL BAFF inhibitor, showing a similar profile of eGFR stabilization through 2 years and 1 year with [povetacicept], the dual APRIL/BAFF inhibitor in Phase II. So it appears as though both agents, both mechanisms, selective APRIL or dual APRIL/BAFF are both effective at stabilizing eGFR, but it really adds to our conviction that selective APRIL is the preferred strategy because it provides that full eGFR stabilization with the most targeted approach, the least broadly immunosuppressive a way to provide that disease-modifying benefit to IgAN patients.

Maybe just move on to the commercial market. So the Otsuka launch, I think, continues to outperform and probably beyond some of the lofty expectations that some people are going in. But when you look at that and you position that against Vera, who is just launching, Vertex, who are likely to have a launch in the coming months. How do you think about the commercial opportunity in front of you coming on what is likely to be in a couple of years' time or a few years' time?

Yes, it's a great question. And we remain convinced this is a very significant commercial opportunity. In the U.S., there's about 170,000 IgAN patients. 60% to 75% of those are above that 0.5 gram a day threshold that we talked about. So they're at risk for progression and need more advanced therapies like a B-cell agent, which are all the ones that you mentioned are B-cell agents. The KDIGO guidelines actually very explicitly say you need to treat all IgAN patients with an agent that depletes pathogenic IgA. So we think that, that class is going to become foundational and really be used extensively. We're very encouraged by the uptake of sibeprenlimab and the big demand for these agents. We do think that they're moving into that frontline foundational position.

But we think it's a big market. So if you look at the 170,000 times 0.6 to 0.7 for the people about 0.5 grams a day and then multiply that by the price, which sibeprenlimab is priced at $390,000 a year, you very quickly get to very large numbers. So there's room for multiple entrants. And -- we also think that the market is going to take a little while to fully develop. Right now, there's a segment of nephrologists that are very interested in IgAN and primary GNs and spend a lot of time at the conferences in the literature, we're in the studies.

And those are the ones right now you're probably seeing putting all their patients on sibeprenlimab. But there are -- there's a big contingent of nephrologists that practice in the community, they're in dialysis centers treating kind of generalized CKD that will take some time to develop. And so that's why we're kind of happy to have Otsuka and Vertex and Vera out there kind of educating the market and creating that demand. And I think it will give us a good market to launch into when JADE101 gets to market.

And so you've guided to the Phase II data next year. So when that does come, can you just walk us through what success looks like? And I don't just mean that against the parameters of the study. But as you know, this is becoming a competitive field, and we're all going to make cross-trial comparisons to that. So maybe just define what success looks like, again, within the parameters of the study and in the competitive landscape.

Yes. So the Phase II study started back in May. It's a small open-label trial in 30 IgAN patients at risk for progression, similar patient population to what will be studied in Phase III, and it's divided across 2 separate cohorts with 2 different dosing strategies. All patients will receive a 700-milligram loading dose of JADE101. All will receive 350 milligrams beginning at week 4. And then 1 cohort of 15 will receive Q8-week maintenance dosing and the other will receive Q12 maintenance dosing. So it's a relatively small sample size, but we do expect to be able to deliver the disease-modifying benefit that other agents have shown.

So there's deep reductions in galactose-deficient IgA1, the pathogenic variant, resolution of hematuria, reductions in proteinuria and the eGFR stabilization we've talked about already. So that would be success for us to be able to show that full disease-modifying benefit of APRIL inhibition with a Q12-week dosing interval. We think that would deliver a very meaningful benefit and value to the patient population. We have designed the study with this loading dose.

So we would hope to see these rapid IgA reductions that we've seen in Phase I healthy volunteers and hopeful that may translate into improved proteinuria reductions earlier in the treatment landscape. But we do want to be realistic with expectations of a 15-patient cohort given the biologic variability in proteinuria that we don't want to anchor too much around setting like specific thresholds of expectations. But the full disease-modifying benefit of APRIL inhibition with 12 weekly maintenance dosing would be an incredible profile to take forward.

Got you. And you mentioned how you're moving forward in Phase III without waiting for that to sort of read out. So what can you say about the Phase III design? When does it start? When can you have data in hand?

Yes. So we have guided that we plan to start the Phase III in the first half of 2027, so next year. So really focused on operationalizing that right now. The study in design will be similar to the Phase II with those 2 dosing interviews, intervals are placebo-controlled. There has been significant evolution on the Phase III study design front. The FDA requested a consortium meeting with the NKF back in April, which consisted of regulators, KOLs in the IgAN space, sponsors as well as a strong voice from IgAN patients, really focused on what the novel Phase III study designs look like in this evolved setting of new therapies approved, particularly within the U.S., recognizing that it will be challenging to maintain the traditional 2-year placebo-controlled trials given the available therapies that patients have options for.

What's been great to see with these data sets from the first-generation agents is that large and early separation in eGFR, you don't need 2 years of placebo controlled to see an eGFR benefit. The benefit you see at 1 year is predictive of the benefit you see at 2 years with this true stabilization versus the 5 to 6 ml per minute decline on the placebo group. So we do anticipate a shorter duration of a placebo-controlled trial, likely a 12-month study with the key endpoints of proteinuria and eGFR for full traditional approval. Originally, 9-month proteinuria was used to support accelerated approval with 2-year eGFR data confirmatory for full approval.

So we think that Phase III study design is going to be very efficient. There's a lot of excitement about APRIL inhibitors, particularly in the wake of the sibeprenlimab data a couple of months ago, showing true eGFR stabilization. Sibeprenlimab is not available globally where these trials are conducted. So the only way to access a disease-modifying therapy like this is through clinical trials. So we do think there will be significant enthusiasm for that, particularly in the setting of only a 12-month placebo-controlled period, where the study is randomized 2:1 active to placebo and all participants are guaranteed a long-term open-label extension with JADE101. So really excited about this evolution and think there's a very efficient path to develop JADE101 through full approval.

All right. Last question on JADE101. I don't want to move on to the rest of the pipeline. So just beyond IgA nephropathy, how are you thinking about where else JADE101 can go? I mean, bearing in mind, you know that the commercial market in IgAN is already turning out to be quite large. So how can you differentiate beyond just that one indication?

Yes. So this is something we're spending time thinking about. Obviously, IgAN is a big opportunity like you mentioned. But what's really interesting about this profile is you knock down IgA robustly as we've talked about. IgG is relatively spared, so stays pretty intact. But then you do also get large drops in IgM, sort of similar to what you see in IgA. So we do think there's a couple of IgM-mediated diseases that are quite attractive. One in particular is multifocal motor neuropathy, which is an indication that is quite rare, but with this pricing can support entry with JADE101 -- and it's something argenx is going after with a complement inhibitor, but we believe we can go upstream and be disease-modifying.

And there's a couple of others as well like anti-MAG neuropathy that we're exploring. So those are things we're considering putting into a basket trial just to get a signal there and then see where we go from there. So that's something we're actively preparing. On the competitive front, we know cibiprinlimab is actually entering a number of different indications that we're watching very carefully. They've actually entered with sibeprenlimab with their selective anti-APRIL into a Sjogren's Phase II study that is anticipated to read out next year. So we're going to watch that very carefully. If that does end up being positive, we think we can have a really good opportunity in that big indication. And they've also announced they're going into FSGS, minimal change disease and primary membranous nephropathy. So those are all potential areas that we can move into rapidly if there is a proof of concept. So as you mentioned, large potential for JADE101.

All right. Let's move on to JADE201. So it's an anti-BAFF receptor antibody. So maybe just walk us through how it differentiates from -- I know Novartis is a drug that's comp here and maybe some other anti-BAFF programs in development.

Yes. We are excited about the dual mechanism of action of JADE201. It's an afucosylated half-life extended anti-BAFF receptor monoclonal antibody. So really following in the footsteps of ianalumab from Novartis, which shares this dual MOA. It uses enhanced effector function mediated ADCC to rapidly and deeply deplete B cells, but also it has a second mechanism of action in that it binds the BAFF receptor and pharmacologically blocks. So it blocks this really important proactivation, proproliferation, pro-inflammatory, pro survival signal in B cells. And that's particularly important in the tissues where autoreactive and pathogenic B cells reside and are often not susceptible to ADCC-mediated depletion because of the sparse availability of effector cells like NK cells.

So in that setting, we can block the BAFF receptor and provide deeper tissue depletion of these pathogenic B cells and also block the compensatory increase in BAFF that drives B cell repopulation that happens with all B-cell depleters. So really excited about getting at the source of pathogenic B cells with this MOA. Ianalumab has very strong pharmacologic characteristics. It's a strong binder with high affinity and a very potent B-cell depleter. It's one limitation really is it has a short human half-life and to maximize the benefit of that second mechanism of action, the sustained BAFF receptor blockade to have the tissue benefit and blocking the repopulation signal. We've designed JADE201 with half-life extension mutations to be able to cover the receptor for extended periods of time to provide better receptor occupancy to potentially drive better clinical activity and do so with a less frequent convenient subcutaneous dosing profile.

Great. So yes, I mean, Novartis' drug, it seems like it's going to be the first approved in Sjogren's. But I don't know if you mentioned this, but the efficacy there has been fairly modest, right? So I guess just relating it back to how you feel about the mechanism of JADE201. So how can it meaningfully push on efficacy? Is it that half-life point? Is it something else with a deeper penetration in the tissue?

Yes. So the data set in Sjogren's with ianalumab is really interesting. And some of what you mentioned with the smaller treatment effects versus placebo are probably representative of some of the challenges in Sjogren's specifically as a disease in terms of the heterogeneity of the disease population, the ability of STI, the primary endpoint to reliably capture disease activity and the very large placebo responses that are observed in that study. When you look at the baseline characteristics in that study that ESSDAI was approximately 12 on average and ianalumab reduced that to 6. So a 50% treatment effect is very large and a very impressive reduction in disease activity. The problem is the placebo went down by 4.5 to 5 such that the treatment benefit, while statistically significant, wasn't as large as we'd hoped.

They do demonstrate very deep circulating B-cell depletion in that study. They also demonstrated in a repeat salivary gland biopsy, 84% decrease in B-cell intensity. So really demonstrating effective activity within the disease tissue. So anything about the efficacy is probably related to the disease rather than the MOA. Interestingly, what they showed in that study is they evaluated 2 different dose intervals, a Q4-week dose, which provided the deep B-cell depletion and receptor occupancy for most of that dosing interval and a Q12-week dosing interval, which provided the B-cell depletion, but not the receptor occupancy throughout the dosing interval.

The Q4-week interval performed much stronger than the Q12 week, which missed, showing the importance of receptor occupancy against the BAFF receptor in driving efficacy. So we do think with JADE101 by design, its extended half-life and ability to cover the BAFF receptor through an extended dosing interval may provide some efficacy advantages relative to ianalumab. But we're not sure whether for the reasons we talked about, the complexity of the disease, the heterogeneity, the challenges with the endpoints of placebo responses, whether that would be a prioritized indication for Jade right now.

One minute left. So I want to sneak one in on JADE301. So I guess, why are you excited about this drug? -- we now have an approved product in the indication that certainly a lot of people are excited about. But beyond that, what's going to be the unmet need do you think in the future? And how can JADE301 sort of ultimately fit that?

Yes, happy to take it. So agree, exciting that brepocitinib is approved, and I think that will raise disease awareness. But touching on what Tom said, this is a -- dermatomyositis is a disease of both very painful itchy skin lesions and also neuromuscular issues. And I think looking at the dazukibart data Phase II, I give Pfizer a lot of credit because they went into a very moderate to severe patient population with skin manifestations, and that's historically been more difficult to treat. And if you look at the CDASI, which is the outcome measure, they had a reduction of 14.5 points or sorry, an improvement. Compare that to brepocitinib, they were about 4.5.

So I think what we see because the interferon beta signature in this disease is so strong that you're having a much more outsized improvement with a drug that's focusing on interferon beta as opposed to a pan immune suppressor like brepocitinib. So I think from the standpoint of treating the disease symptoms, which are the most impactful to patients, which are those painful itchy lesions. They lose sleep, they're very fatigued. That in and of itself has us excited and has all the rheumatologists we've spoken to who treat this disease are similarly excited because their patients are mostly complaining about their skin symptoms.

That being said, even though they had a smaller cohort of patients, numerically, they showed a higher change in that total improvement score, or TIS, and that's representative of the neuromuscular function as well. So seem to be beating brepocitinib on the skin and early Phase II data indicates they could possibly be better in the neuromuscular component as well. They're dosed IV, we're dosed subcu, we're half-life extended. So hoping to have subcu dosing that's more convenient for patients, directly addressing the underlying pathogenesis of the disease.

Great. Well, we're up on time. Thanks for the great overview and the discussion, and thanks for joining us. Good luck, guys.

Good morning, and welcome to the Jade Biosciences conference call and webcast to discuss JADE101 Phase I healthy volunteer study results. [Operator Instructions]

Now I'd like to turn it over to Tom Frohlich, Chief Executive Officer of Jade Biosciences.

Thank you, and good morning, everyone. Earlier today, we announced positive interim results from our Phase I trial for JADE101, a potentially best-in-class, fully human monoclonal antibody designed to selectively inhibit A Proliferation-Inducing Ligand or APRIL. APRIL is a key driver of pathogenic IgA production in patients with IgA nephropathy, a progressive autoimmune kidney disease that presents a lifetime risk of kidney failure.

On today's call, we'll walk you through interim results for the Phase I trial for JADE101 and our development plans for this candidate.

Moving to Slide 2. Before we begin, I'd like to note that today's discussion will include forward-looking statements. These include statements about Jade's development plans and the therapeutic profile and potential of JADE101 and our cash runway. Because such statements deal with future events and are subject to many risks and uncertainties, actual results may differ materially from those in the forward-looking statements.

We will also be making comparisons of data across separate non-head-to-head studies and caution should be exercised when drawing conclusions from such comparisons as the data may not be directly comparable. For a full discussion of risks and uncertainties associated with our business, please review the cautionary language included on the disclaimer slide of this presentation and in our latest SEC filings.

I'm joined today by Dr. Andrew King, Jade's President of Research and Development.

Slide 3. Let me start with the main takeaway from today's call. I'm very pleased to present that the data from the JADE101 Phase I trial exceeded our expectations. The JADE101 results demonstrated deep and durable reductions in IgA, a favorable tolerability profile and support the potential for every 12-week maintenance dosing with a single subcutaneous injection.

The emerging profile of JADE101 is highly differentiated and has the potential to provide a meaningful advance for patients with IgAN. These are patients who are often diagnosed as young adults and require lifelong therapy. These results are especially meaningful as biomarkers from healthy volunteer studies translate closely to anticipated results in IgAN patients and provide an extensive characterization of JADE101's profile.

This Phase I tested whether the design features of JADE101 with its ultra-high potency, engineered half-life extension, and selective anti-APRIL MoA could deliver a differentiated target product profile in IgAN.

Results of this Phase I trial met or exceeded all four of our key objectives. The first objective was to design a dosing interval of at least every eight weeks, determined by the duration of IgA suppression prior to recovery. I'm pleased to report, and as Andrew will describe in more detail, we believe the depth and duration of IgA reductions observed with a single dose of JADE101 supports the potential for a maintenance dosing interval of every 12 weeks.

The second objective was to demonstrate a favorable, well-tolerated safety profile, generally consistent with prior experience with selective anti-APRILs. JADE101 did, in fact, have a favorable safety results at all tested doses, was well tolerated locally with only infrequent mild or moderate injection site reactions and no cases of hypogammaglobulinemia. The safety profile was generally consistent with what was seen with selective APRIL inhibition, which selectively targets pathogenic plasma cells involved in IgAN without impacting the rest of the B cell repertoire.

Third and most importantly, the aim was to achieve IgA reductions of 55% sustained for eight weeks. 55% was our target as it approximates the largest IgA reduction previously observed after a single dose of first-generation anti-APRILs in healthy volunteers. JADE101 performed above our 55% IgA reduction objectives, demonstrating rapid reductions in IgA of approximately 70% following a single dose of JADE101 at 700 milligrams, which was sustained at 12 weeks. This magnitude of production is the result of the IgA lowering potency of JADE101, which is estimated to be 375-fold higher than sibeprenlimab and 26-fold higher than povetacicept.

Our pharmacodynamic modeling suggests we can sustain these reductions with a single 350 milligram injection every 12 weeks. This gives us a high degree of confidence in JADE101 delivering best-in-class IgA reductions with a Q12-week dosing interval. IgA reductions in healthy volunteers have been shown to be highly correlated with the expected clinical activity in IgAN patients. Notably, these IgA reductions were the result of potent, rapid, complete and sustained suppression of APRIL, the upstream driver of IgA and pathogenic IgA production.

Fourth, we wanted to see a dose-dependent exposure and extended half-life and mitigation of target-mediated drug disposition, or TMDD, which has substantially influenced first-generation anti-APRILs. We also wanted to see minimal impact of immunogenicity on exposures or pharmacodynamic responses. The JADE101 PK did demonstrate dose-dependent exposure and as compared to separate prior third-party studies, a half-life approximately 8.7-fold longer than povetacicept and 2.6-fold longer than sibeprenlimab.

We also observed mitigation of TMDD with JADE101 with a threshold estimated to be approximately 2.5-fold lower than what has been reported for sibeprenlimab. In addition, we have not observed any apparent impact of antidrug antibodies on PK and PD, where clinically meaningful impact of ADA and plasma exposure has been reported with sibeprenlimab.

These data, which Andrew will review in more detail, supports JADE101 potential to deliver best-in-class clinical activity with an infrequent Q12-week dosing profile for IgAN patients. With these data in hand and a high degree of conviction in the clinical profile and dosing regimen, we've initiated a Phase II trial of JADE101 with results anticipated in 2027. We also plan to initiate a Phase III pivotal trial of JADE101 in the first half of 2027, pending FDA requirements.

Turning to Slide 4 now. The Phase I results are a direct reflection of the novel JADE101 design. JADE101 was selected through a de novo antibody discovery campaign and binds APRIL with ultra-high affinity in the femtomolar range. This level of binding affinity is intended to enable potent and rapid APRIL neutralization at low drug concentrations.

In addition, JADE101 is designed to be selective for APRIL. That matters because in IgAN, the goal is to reduce pathogenic IgA while avoiding broader immune suppression that may come with less selective B cell pathway modulation. JADE101 is a fully human antibody designed to bind to a novel epitope, which avoids the formation of large molecular weight complexes observed in the first-generation anti-April monoclonal antibodies.

Large complexes can increase risk of immunogenicity, which has been observed with sibeprenlimab. Furthermore, JADE101 was designed to support durable and predictable exposure. The molecule incorporates a validated YTE Fc modification for half-life extension to support a longer dosing interval. By combining ultra-high affinity, avoidance of large complex formation and half-life extension, JADE101 was designed to have best-in-class clinical activity and a convenient dosing regimen.

On Slide 5, IgAN represents a substantial commercial opportunity with approximately 169,000 patients in the U.S. and more than 1 million patients globally. Based on international guidelines, we estimate that 60% to 75% of patients in the U.S. may be eligible for treatment. With recent approvals, increasing recognition of the disease and evolving treatment guidelines, we believe the U.S. IgAN market alone has the potential to exceed $20 billion with significant additional opportunity outside the U.S.

Moving to Slide 6. IgAN is a serious progressive autoimmune kidney disease with a high lifetime risk of kidney failure. Patients are often diagnosed as young adults between the ages of 16 and 35 and many require treatment over decades. Convenience is crucial in this disease as IgAN patients are often otherwise healthy young adults living with a generally asymptomatic but progressive kidney disease. For this population, a therapy that can deliver sustained disease control with less frequent dosing could represent an important advantage.

Persistent proteinuria is associated with an increased risk of kidney failure with higher levels of proteinuria linked with a greater lifetime risk. This risk begins at a low threshold of proteinuria that historically may have been viewed as relatively modest. There remains a need for a new medication that can meaningfully reduce proteinuria, preserve kidney function and be suitable for long-term use.

On Slide 7, the KDIGO guidelines, which direct the treatment of IgAN globally were updated at 2025, putting greater emphasis on the earlier diagnosis and intervention to prevent kidney failure and highlighting the need for effective disease-modifying medication. They call for IgAN patients to be treated with an agent that depletes galactose-deficient IgA1, the pathogenic immune driver for IgAN in addition to agents that offer supportive care by acting locally in the kidney to slow nephron loss.

The guidelines now identify patients with proteinuria greater than 0.5 gram per day as being at risk of progressive kidney function loss compared with the previous target of greater than 1 gram per day. KDIGO also lowered the treatment target, recommending proteinuria be reduced to less than 0.5 gram per day and ideally less than 0.3 grams per day. These changes position B cell modulators such as anti-APRIL therapies to become foundational treatment in IgAN, given their ability to significantly reduce pathogenic IgA, proteinuria and stabilize kidney function.

Moving to Slide 8. This slide shows two important relationships, which highlight the predictive nature of healthy volunteer data to clinical outcomes in IgAN.

On the left, you can see that IgA reductions observed in healthy volunteers with APRIL neutralization are highly correlated with the IgA reductions subsequently observed in IgAN patients. That means that healthy volunteer IgA data are not just a pharmacodynamic signal in isolation, they have shown strong consistency with what is observed in patients.

On the right, this shows the link between biomarker response and clinical activity. Early IgA reductions in IgAN patients is highly correlated with later reductions in proteinuria. That is why the depth and durability of IgA reductions we observed with JADE101 support our confidence in the clinical profile and dosing regimen as we advance JADE101 into IgAN patient studies.

With that, I'll turn it over to Andrew to walk through the Phase I data in detail.

Thank you, Tom, and good morning, everyone. I'm excited to walk you through the positive interim results for JADE101.

On Slide 10 now. First, I'll describe the trial design. This is a first-in-human randomized, double-blind, placebo-controlled, single ascending dose study in 32 healthy volunteers. Each participant received a single subcutaneous dose of JADE101 or placebo. The 4 cohorts studied spanned a wide exposure range.

The dose levels were intentionally selected to map to our intended clinical dosing strategy. A high concentration formulation of JADE101 at 175 milligrams per ml was administered subcutaneously, which enables a 350-milligram dose to be delivered in a single injection compatible with future prefilled syringe or auto injector delivery.

Cohort 1 was administered a low dose of 175 milligrams intended to be transiently pharmacologically active to capture the onset and recovery of APRIL-mediated responses. The Cohort 2 dose of 350 milligrams was the design to represent a potential maintenance dose, aligned with a convenient, patient-friendly, single subcutaneous injection. This is our planned maintenance dose for Phase II and Phase III clinical trials.

The 700-milligram dose in the third cohort is our planned induction dose for Phase II and Phase III. Finally, Cohort 4 received a 1,400-milligram dose to enable full characterization of the safety profile of JADE101. This interim analysis presents data with 5 to 8 months of follow-up across the sequentially dose cohort as of the data cutoff of April 14, 2026.

This study randomized participants 6 to 2 active to placebo per cohort. As the trial is ongoing, the interim baseline and safety data today are presented in a blinded format, pooling active, and placebo. PK and PD data are reported per treatment group. This approach allows individual treatment assignments to remain blinded, preserving ongoing study integrity.

The primary objective of this study is to characterize the safety and tolerability of JADE101. The secondary objective is to assess JADE101's PK profile. Of most translational relevance, we are characterizing the depth and duration of IgA reduction. We are also assessing target engagement through free-APRIL reductions and measuring other immunoglobulins including IgG, M and E.

Finally, we are exploring whether immunogenicity has any impact on the pharmacokinetics and pharmacodynamics of JADE101.

On Slide 11, the baseline characteristics observed were consistent with a typical healthy volunteer population and were generally balanced across those groups. Gender distribution was even overall with comparable BMI across cohorts. The population included a mix of racial backgrounds. These baseline characteristics support the generalizability of these Phase I findings.

Moving to Slide 12. JADE101 demonstrated a favorable safety profile and was well tolerated across all evaluated dose levels. Across the full study population, there were no deaths, no serious adverse events, no severe treatment-emergent adverse events and no discontinuations due to adverse events. All treatment-emergent adverse events were mild or moderate in severity. We also observed no clinically significant changes in ECGs or vital signs and no trends or signals in safety labs.

JADE101 was well tolerated locally following subcutaneous administration with infrequent mild or moderate injection site reactions. Injection site erythema was reported in 3 of 32 participants or 9%, and mild injection site pain was reported in 1 of 32 participants or 3%. We observed no hypogammaglobulinemia defined as IgG less than or equal to 3 grams per liter. This is consistent with JADE101 selective anti-APRIL mechanism, not showing evidence of broad immunosuppression.

Importantly, we observed no apparent impact of antidrug antibodies on PK or PD. The table on the right summarizes the overall safety results. Across all cohorts, 24 of 32 participants or 75% experienced at least 1 treatment-emergent adverse event. The most common events occurring in more than 2 participants were generally typical of a healthy volunteer study conducted with an up to 8-month follow-up as of the data cutoff, including headache, upper respiratory tract infection, injection site erythema, oropharyngeal pain, and pyrexia. Upper respiratory tract infection AEs were numerically slightly lower in the JADE101 treated participants than placebo. Overall, these results support the potential for a favorable safety profile of JADE101 in IgAN patients.

Moving to Slide 13. We are especially encouraged by the magnitude and duration of IgA reductions produced by single ascending doses of JADE101, exceeding those observed with the first-generation APRIL inhibitors in healthy volunteers.

On the left-hand chart, the IgA reductions observed with JADE101 were dose-dependent in both depth and duration of response. Reductions in IgA of at least 50% were observed at all doses tested, and IgA reductions of approximately 70% decrease from baseline were observed at a dose of 700 milligrams. We believe this represents the largest IgA reduction reported following a single dose for a B cell modulator in healthy volunteers.

The single 700-milligram dose is the key dose to focus on because it is predicted to reflect the depth and duration of IgA reduction in IgAN patients with repeat dosing of JADE101 in response to our planned IgAN dosing strategy, which is a 700-milligram induction dose, followed by Q12-week maintenance dosing of 350 milligrams beginning four weeks after reduction.

We will present additional details on this dosing strategy in the following slides, including our pharmacodynamic modeling and simulations. At the 700-milligram dose, JADE101 produced an approximately 70% reduction in serum IgA that was sustained at 12 weeks post dose. The IgA profile observed at the 700-milligram dose supports the potential for Q12-week maintenance dosing with JADE101. Notably, similar peak IgA reductions are seen with both the 700-milligram and 1,400-milligram dose, which suggests we are maximizing the clinical activity available to the mechanism with our go-forward dosing strategy.

On the right-hand side, we put this into competitive context using publicly available data. Cross-trial comparisons have limitations and should be viewed as hypothesis generating. However, this comparison is useful because it shows the comparative magnitude of IgA reduction at clinically relevant single doses in healthy volunteers.

At their respective Phase III doses, sibeprenlimab and povetacicept produced peak IgA reductions of between 50% and 55% following a single dose, numerically lower than the approximately 70% reduction observed with JADE101 at 700 milligrams, the planned induction dose. Higher doses of sibeprenlimab and povetacicept, which were not advanced into Phase III, also did not match the approximately 70% reduction observed with JADE101 at the 700-milligram induction dose.

Turning to Slide 14. The exposure response observed for JADE101 to drive and sustain IgA reductions in this Phase I study allows for a comparative assessment of JADE101's in vivo IgA lowering potency relative to the first-generation anti-APRILs based on an analysis of their publicly available data. JADE101 demonstrated remarkable in vivo IgA lowering potency with an EC50 to reduce serum IgA in humans of approximately 10 picomolar. JADE101 demonstrated a lower IgA EC50 than reported for the first-generation agents, including 26-fold lower than povetacicept and 379-fold lower than sibeprenlimab.

The figure on the right side of this slide shows a strong association between in vitro binding affinity to human APRIL and in vivo potency to reduce serum IgA in humans with an R-squared value of 0.9. This suggests that the in vivo potency of each agent to lower IgA can be largely explained based solely on April binding affinity. JADE101's ultra-high binding affinity is now manifesting in this healthy volunteer study as ultra-potent in vivo IgA lowering and resulting in rapid, deep and sustained IgA reductions.

As a result of JADE101's IgA lowering potency in humans, only very low plasma concentrations of JADE101 and needed to sustain IgA reductions. In this chart, you could also see the relationship between potency and dosing interval. Atacicept and zigakibart have relatively low APRIL binding affinities and therefore, must be dosed every week or every two weeks, respectively.

Sibeprenlimab is a more potent than both and is dosed every four weeks. Povetacicept, more potent still is also dosed every four weeks, though it only has a 2.8-day human half-life. JADE101 is more potent than povetacicept to lower IgA and has an 8.7-fold longer half-life, again, giving us confidence in the Q12-week dosing interval.

Moving to Slide 15. We further described JADE101 pharmacodynamic modeling and clinical trial simulations. Population-based simulations were conducted, leveraging all publicly available data, of which we are aware, across APRIL targeted development programs to generate a representative virtual IgAN population and predict targeted biomarker responses. The model is most richly informed by the detailed exposure response analysis and data contained in the FDA review documents for sibeprenlimab's approval.

This model-based framework accurately recapitulates model-based outcomes for other anti-APRIL agents and reliably captures observed serum IgA reductions in patients with IgAN across Phase II and Phase III clinical trials. Leveraging the entirety of our biomarker-rich first-in-human data and our planned dosing strategy, JADE101 is predicted to potentially deliver best-in-class IgA reductions more rapidly than the first generation programs and sustain those responses with convenient subcutaneous dosing as infrequently as every 12 weeks.

The solid lines represent the median values across 500 simulated trials, and the shaded areas represent the 95th percentile of prediction -- predicted population-based variability. Although modeling is inherently limited, we believe the simulations are informative as we advance JADE101 into patients. We believe JADE101 has the potential to achieve best-in-class IgA reductions more rapidly than first-generation anti-APRIL agents, which require multiple doses. The potential for a faster onset of peak IgA response offers the potential for improved benefits on key IgAN clinical endpoints such as proteinuria reduction at 9 months. The simulations also suggest the potential for overall deeper IgA reductions with JADE101 at the population level.

The modeled IgA curves suggest JADE101 can maintain the deep IgA reductions that are induced by 700 milligram induction dose with a Q12-week maintenance dosing of a single subcutaneous injection of 350 milligrams beginning at week 4. Initiating maintenance dosing at week 4, while TMDD is fully saturated from the induction dose provides a strong pharmacokinetic and pharmacodynamic foundation to sustain these responses. The potential for best-in-class IgA reductions sustained with Q12-week JADE101 dosing would represent a highly differentiated profile.

On Slide 16, the dose-dependent pharmacokinetic profile of JADE101 and the rapid and complete free APRIL suppression across all doses enabled these deep and durable IgA reductions we just discussed. The PK profile of JADE101 is displayed in the left chart. As doses increase from 175 to 1,400 milligrams, we see increases in exposure and increasing evidence of YTE-mediated reductions in linear clearance. A hallmark of the impact of saturation of TMDD associated with the anti-APRIL [ mAb ].

We observed an extended half-life relative to the first-generation agents of 24.2 days. This is meaningfully longer than publicly reported data for the first-generation anti-APRIL targeting agent dosed every 4 weeks, including approximately 8.7-fold longer than the 2.8-day half-life reported for the povetacicept 80 milligram dose and approximately 2.6-fold longer than the sibeprenlimab 9.3-day half-life reported on an FDA label for the 400 milligram subcutaneous dose.

This extended half-life combined with JADE101's higher in vivo potency to reduce serum IgA in humans through low JADE101 plasma concentrations supports a Q12-week maintenance dosing interval for JADE101. The estimated TMDD threshold of JADE101 was approximately 2.5-fold lower that observed in the reported sibeprenlimab clinical PK profiles TMDD arises from high affinity binding of the drug to its target, in this case, APRIL, which can act as a clearance sink and drive rapid nonlinear elimination at lower concentrations.

As exposure increases and target binding becomes saturated, clearance transitions towards a slower linear non-target mediated process. First-generation anti-APRIL monoclonal antibodies appear to be substantially influenced by TMDD. In this context, it is notable that JADE101 achieved saturation of TMDD at lower concentrations than reported for sibeprenlimab. This behavior is consistent with the ultra-high binding affinity of JADE101, which likely facilitates, more efficient target engagement, and earlier saturation of APRIL-mediated clearance pathways.

On the right free-APRIL panel, you can see that JADE101 produced rapid and complete suppression of serum free-APRIL across all evaluated doses. Remarkably, complete free-APRIL suppression was observed as early as 2 hours after subcutaneous administration, reflective of very potent inhibition of APRIL even at low serum concentrations of JADE101. The duration of free-APRIL suppression was dose dependent. At the 700 milligram dose, greater than 90% APRIL suppression was sustained for a median of 85 days, based on noncompartmental analysis of individual participant profiles.

Slide 17 shows the impact of JADE101 on the broader immunoglobulin profile, which is consistent with the selective anti-APRIL mechanism of action. IgG reductions were modest, consistent with a relatively IgG sparing effect from selective APRIL inhibition. The magnitude of IgG lowering observed with JADE101 was consistent with the first-generation anti-APRILs. There were no cases of hypogammaglobulinemia.

The profile of IgM reduction produced by JADE101 was similar to that observed in IgA, again as expected with the anti-APRIL MoA and consistent with the first-generation anti-APRIL agents. We also observed an approximately 50% reduction in IgE with JADE101.

Moving to Slide 19. We'll walk through our dosing strategy in Phase II and planned Phase III clinical trials. For Phase II and Phase III, following an initial 700 milligram induction dose, intended to drive 70% IgA reduction at earlier time points. We plan to evaluate 2 dose intervals.

A single subcutaneous 350 milligram maintenance dose, administered every 12 or every 8 weeks with the goal to optimize the clinical activity and convenience in a best-in-class profile. Including 2 doses in future patient trials, may allow us to accelerate the initiation of a pivotal Phase III trial without waiting for Phase II data. Incorporating multiple doses in a registrational trial supports global regulatory expectations for formal dose finding in patients and it allows us to accelerate the overall JADE101 development plan.

As described in the previous slides, our Q12 maintenance dose is designed to deliver best-in-class IgA reductions with faster and numerically greater IgA reductions than first-generation B cell modulators. We chose Q8 as our second dose interval to test if more intense dosing will add any additional clinical benefit. Our pharmacodynamic modeling demonstrates comparable IgA reductions in both duration and depth for both Q12 and Q8 intervals. We believe this dosing strategy positions us to move rapidly in the development of JADE101 while delivering a potentially best-in-class clinical profile.

Turning to Slide 20. We recently initiated the Phase II JUNIPER trial for JADE101 in IgAN, and disclosed last week that the first participant has been dosed. This is an open-label trial where all participants received active JADE101 with a convenient and infrequent subcutaneous administration. The trial is enrolling adults who have been diagnosed with biopsy-confirmed primary IgAN who continue to display a urine protein-to-creatinine ratio, or UPCR level from a 24-hour urine sample of at least 0.75 grams per gram and an eGFR of 30 or higher, despite already being on a stable standard of care for at least 12 weeks.

This patient population remains at high risk for disease progression and requires a foundational disease-modifying therapy. We will evaluate safety and tolerability and will also assess key efficacy measures, including UPCR over time, UPCR reductions below key proteinuria thresholds of less than 0.5 grams per day and less than 0.3 grams per day and eGFR over time. In addition, we'll measure key pharmacodynamic biomarkers, including pathogenic galactose-deficient IgA 1.

All participants are expected to receive an induction dose of 700 milligram at the start of treatment and then randomized 1:1 to maintenance doses of 350 milligram, Q8 weeks or Q12 weeks beginning 4 weeks after induction for a 100-week treatment period. We aim to enroll 30 participants in this trial and expect to report interim clinical data in 2027.

With that, I'll now hand the call back to Tom.

Thanks, Andrew. The Phase I data reviewed today provides us with the conviction that JADE101 is highly differentiated and can offer a significant advance for patients with IgAN, a large commercial opportunity, representing a total addressable market of more than $20 billion in the U.S. alone. The results demonstrate JADE101 has the potential to be a best-in-disease molecule with the potential to capture the efficacy available to the anti-April mechanism with convenient Q12-week dosing.

As discussed, the translatability of healthy volunteer biomarker data in IgAN with the anti-APRIL mechanism gives us conviction in JADE101's profile and allows us to move very quickly into patient trials. We've started dosing participants in our Phase II JUNIPER trial and anticipate interim data in 2027. We continue to explore opportunities to accelerate the initiation of a Phase III trial, which we currently anticipate starting in the first half of 2027 pending FDA requirements.

Beyond JADE101, we are developing potentially best-in-class therapies for several autoimmune diseases. We have two additional programs that are rapidly advancing. JADE201 is a half-life extended afucosylated monoclonal antibody targeting BAFF-receptor, the B cell activating factor -- B cell -- receptor. We recently initiated a first-in-human study evaluating JADE201 in patients with rheumatoid arthritis from which we anticipate interim data in 2027.

We also have a third antibody program, JADE301, which is expected to enter the clinic in the first half of 2027. Additional details on this program are expected to be shared in the second half of this year. With cash runway expected into the first half of 2028, Jade is well capitalized to pursue an aggressive development plan for JADE101 while also advancing JADE201 and JADE301 through key data readouts.

Just as importantly, we continue to build a team of highly experienced drug developers and company builders. This combination of innovative science, strong financial backing and seasoned talent gives us the foundation to move quickly and decisively. We are proud of the progress we have made and are excited for the milestone-rich period ahead. Above all, we are motivated by the potential impact our therapies may have for patients living with autoimmune disease.

With that, I'll hand it back to the operator to open the line for questions.

[Operator Instructions] Our first question comes from the line of Akash Tewari with Jefferies.

This is Alexia on for Akash. So given that we're seeing both faster and deeper IgA reduction from JADE101 versus first-generation agents, could we potentially expect to see better efficacy on proteinuria come Phase II?

Yes. Thanks, Alexia. It's a good question. Yes, definitely, IgA reductions have been closely correlated to the proteinuria reductions expected at the 36-week time point. So we do anticipate having that fast onset of action due to the induction dose to be able to reach those maximal reductions in IgA at very, very early time points, and that could drive getting to peak proteinuria reductions also at an earlier time point.

We have seen with the first-generation anti-APRILs that you do see excellent robust reductions in proteinuria at the week 36 or week 40 time point, but then it does look like it does continue to decrease at the 12-month and the 18-month time points. So we can anticipate with JADE101 to achieve those maximum reductions in proteinuria at earlier time points. So we do believe that this gives us a really good opportunity to reach very, very significant levels of proteinuria at those earlier time points. So we're very optimistic that we can show really a best-in-class profile with this convenient dosing format.

Our next question comes from the line of Tyler Van Buren with TD Cowen.

Congratulations on the excellent early data, which clearly exceeded expectations. A couple for you. The first one is just, yes, so the translatability of IgA reduction to proteinuria is super strong and fairly obvious based upon the nearly perfect correlation coefficient of the 0.92. But one of the more common questions I get from investors is if there's room for further improvement on eGFR, given what we've already seen with the other agents in the class. So curious to get your opinion there.

And then the second question is, can you provide any brief preliminary thoughts on the outcome of the recent NKF meeting? What are the resulting action items? And how it impacts your future interactions with the FDA and if it's gating?

Thanks, Tyler. Really great questions. Yes, we're really encouraged by the early outcomes of that NKF workshop. Just as a quick reminder to those who may not be as familiar, the FDA asked the NKF to pull together a group of industry sponsors, patient groups, KOLs and the FDA themselves to discuss what does a contemporary trial in IgAN properly look like because there's an increasing recognition that a 2-year placebo-controlled trial is not necessarily ethical for patients to keep them off drug for a 2-year period in age of these very efficacious medications being potentially available and also the feasibility of those trials is a lot lower.

Andrew, you actually attended the workshop and with the team have been looking very, very closely at this. Do you want to take that question and then also the question on eGFR expectations?

Yes. Thanks a lot, Tom. So really encouraged by the conversation at the NKF, clear recognition of the need to reduce placebo exposure in IgAN patients in the clinical trial setting and really look forward to that FDA feedback Tom highlighted around guidance and directions of new study designs. But we do feel confident based on the nature of those discussions and rallying around these key concepts by FDA commentary, sponsors, IgAN patients and global KOLs, there will be an efficient path to Phase III development for disease-modifying anti-APRIL like JADE101 with the potential for large treatment effects.

On the eGFR side of things -- what we've seen now consistently across 4 programs, 2 selective anti-APRIL and 2 dual APRIL/BAFF inhibitors is effective eGFR stabilization, out through 12 to 24 months, depending on follow-up from the individual studies. Really eGFR stabilization is probably the best you can accomplish in the setting of treating IgAN. eGFR decline is generally a result of nephron loss. So it's unlikely you're going to get nephron return. So eGFR stabilization is really the key treatment goal.

You may get some modest increases in eGFR associated with reduced immune complex mediated inflammatory injury to the kidney, but that would be relatively incremental. So long term, the goal is eGFR stabilization. And given the early data across multiple programs, in a short 1- to 2-year trial, it may be difficult to differentiate from that over that short duration of time. However, the goal for treating IgA nephropathy is not just eGFR stabilization over 1 to 2 years, it's really over decades in these young patients that have high lifetime risk of end-stage kidney disease.

And what we know from epidemiological studies is that residual proteinuria is the best predictor of long-term clinical outcomes in IgA nephropathy. And that's why the treatment guidelines, as Tom highlighted, are really focused on producing the largest reductions of proteinuria you can to below 0.5 grams per day and preferably back to within normal range of 0.3 grams per day because of that strong association between proteinuria and longer-term outcomes.

So although we don't think there's a lot of opportunity to differentiate on eGFR over the short-term trials since the other agents are already reporting stabilization, we do think having an agent, as Tom highlighted earlier, with these large and rapid IgA reductions, potentially delivering greater reductions in proteinuria and higher rates of clinical remission would be preferred by nephrologists.

Thank you. Our next question comes from the line of Alex Thomson with Stifel.

Great. Let meadd my congrats on the data as well. Two from us. I guess on expectations for Phase III design here with 2 dose arms, should we expect a trial of similar size to sort of the contemporary Phase IIIs from the first gens? Or how are you thinking about that? And then, in terms of enrolling a Phase II and Phase III trials today, how do you expect IgAN patients in these trials to sort of be similar or different than these other contemporary studies?

Great. Great. Really good questions, Alex. On expectations for Phase III in terms of the trial design -- it's -- we haven't received that guidance yet from the FDA. So we still have to have that interaction. So it's difficult for us to provide too many details. But we do think that the treatment effect sizes of this class are much better characterized than they were previously. The VERTEX study was around a 600-patient trial. The Otsuka trial was in the 500 patients, and we're seeing like p-values that really blow it out of the water.

And so we really do have a better understanding what treatment effect assumptions we need to make. And we don't think that you need a trial size of that magnitude. And you can actually really get -- run a very efficient trial likely sort of in the 400-patient range, even having those 2 dose arms involved. But we will provide more guidance as we have those interactions with the FDA and start initiating that Phase III trial. In terms of enrollment, Andrew, you and the team have been really looking at this and thinking about the patients selection and inclusion criteria. Do you want to provide some context?

Yes, absolutely. So these are global trials. Obviously, the United States is an important component of these studies. But the epidemiology of IgA nephropathy indicates higher prevalence and perhaps higher severity, particularly in Asian populations. So these trials are truly global. Although there have been significant advances in the U.S. with multiple approvals, many of these agents are not broadly available globally, so it won't necessarily impact trial enrollment or the baseline characteristics of the patient population, including the concurrent medications they're on.

The one exception to that is we are seeing increased uptake of SGLT2 inhibitors globally, sequentially across the studies with more recent studies showing significantly higher concurrent SGLT2 inhibitor use. So we do expect that to continue moving forward. However, we're very encouraged by the subgroup analyses that have been reported from multiple agents now that inhibit APRIL selectively or inhibit APRIL and BAFF in combination in that you get the full disease-modifying benefit of APRIL inhibition irrespective of background SGLT2 inhibitor use.

Actually, you tend to numerically get slightly greater reductions in proteinuria if patients are on background SGLT2 inhibitors, perhaps due to better hemodynamic control in that population. So we do think there'll be some evolution in that background therapy, but I think it still shapes up very well for the potential of a selective anti-APRIL, particularly given the global nature of these studies.

Our next question comes from the line of Julian Harrison with BTIG.

Let me add my congratulations on these results. First, definitely I could appreciate the strong translatability from IgA reductions to proteinuria reductions. In light of that, I'm wondering if it's your expectation that you could likely command significant preference, even at parity efficacy versus the approved precedent in IgAN with 1/3 of the injection burden ? Or do you maybe view better efficacy as an important success factor as well at this point?

And then second, it seems like you have line of sight to quarterly dosing and maintenance. So I'm wondering if you could help us better understand the Q8-week maintenance arms in your Phase II and Phase III trials. Is this really just for the sake of dose ranging? Or do you maybe envision Q8-week could be beneficial to as an approved option for some patients?

Thanks, Julian. Yes, two important issues. Yes, we've done some market research to look at what are the choice drivers for uptake of the class of drugs in IgAN. And really, the convenience and efficacy are both going to be key choice drivers for clinicians to drive market share. Obviously, if we can achieve greater levels of proteinuria, then that would be highly attractive and drive share because as Andrew pointed out, that really does define that lifetime risk of disease progression. So if you're getting more patients down to below the KDIGO target of 0.5 gram a day or even back into clinical remission, which is considered below 0.3 grams a day, then that type of a medication would clearly drive a lot of uptake and preference.

But we are seeing that convenience actually is also driving a lot of selection. We actually hear it from the current agents that are in development. There's a lot of attempts to differentiate around some elements like injections volume, the format of the presentation of the auto-injector versus prefilled syringe. But we really know that the ultimate factor in driving convenience is the number of injections, as you point out. So we really do believe that having fewer injections over time for this generally asymptomatic population is actually going to drive a lot of preference. And we have done a small market research to show that, that is, in fact, the case. Even if you kept efficacy fairly constant, that a less frequent dosing interval would drive a lot of uptake for patients.

And given the fact that this is such a large and growing market -- we referenced the figure of $20 billion TAM in the U.S. several times. There's going to be multiple winners here. But we do believe with the emerging profile of JADE101, we can capture a significant part of that. So kind of a nonanswer there where it's both efficacy and convenience are both very, very important drivers of differentiation. We feel like we're extremely well positioned on both.

In terms of the Q12 versus the Q8 weeks, very high level, like we're moving very quickly here. We do plan to initiate that Phase III in the first half of 2027. So we're moving very, very quickly off of Phase I data. And so it is very prudent to take 2 doses forward in that type of situation, but there's obviously other advantages.

And Andrew, do you want to talk through the rationale between the Q12-week and why the Q8-week was selected as a second dose?

Yes. It's really to support acceleration of the program into that pivotal trial. The pharmacodynamic modeling supports the Q12-week maintenance dose sustains those 70% plus IgA reductions induced by the induction dose of 700 milligrams using a 350 milligram Q12 dose. So we believe that will provide the full efficacy available to IgA lowering to the anti-APRIL MoA.

When thinking about the second dose to move forward to do formal dose finding in patients to satisfy global regulatory expectations. Commercially, the extended dosing interval would be Q24, that would make sense. However, due to the impact of TMDD, we don't think that's feasible with JADE101, which makes Q8-week dosing the choice for that second dose arm to explore whether there's any possibility that more intense dosing provides any additional clinical benefit. From our PK/PD modeling, we don't think there'll be any difference in IgA reduction between Q8 week and Q12, but to satisfy formal dose exploration and assess whether more intense dosing provides any meaningful clinical benefit is the rationale for Q8.

Very helpful. congrats again.

Our next question comes from the line of Laura Chico with Wedbush.

Congrats on the data. One for me first on ADAs. I'm not sure if this should be Andrew or Tom, but it doesn't sound like there's any impact on the PK for JADE101 due to ADAs. But perhaps you could remind us on when these impacts manifest with sibeprenlimab? Just trying to understand what gives you the most confidence that JADE101 can avoid ADA interactions? And then separately on -- I'm sorry, go ahead. I'll ask a follow-up then.

Sorry, I was just going to say, Andrew, do you want to take that question?

Yes. Yes, sure thank. So what we saw with the sibeprenlimab profile is ADAs that peaked at around 6 months following initiation of treatment of sibeprenlimab in Phase III. What was particularly impactful of ADA positivity in that study was the clinical impact that had with a 40% decrease in plasma exposure and an approximately 10% decrease in proteinuria reduction versus ADA negativity. So it's really the impact that ADAs have on PK/PD or safety that's of clinical consequence.

JADE101 was designed to be a fully human anti-APRIL monoclonal antibody and was also selected with a novel epitope to avoid the formation of large immune complexes, which can happen when monoclonal antibodies bind trimeric proteins like APRIL and happens when sibeprenlimab binds APRIL. These large immune complexes can increase the risk of immunogenicity. So by design, we try to limit the risk of immunogenicity with JADE101 and are very encouraged by this first in-human data set where we've seen no impact of ADA on PK or PD. And obviously, we'll continue to follow this closely as we move into Phase II and Phase III to assess repeat dosing in IgAN patients.

And then just one follow-up on JUNIPER. I know you're guiding to data in '27, but I'm trying to understand perhaps what type of data should emerge here. Would this be 6-month results, both cohorts? I don't know if you can kind of give a little bit more color on what we should be looking for, for -- from JUNIPER in '27?

Yes. Andrew, do you want to talk through that as well?

Yes, happy to. So we do want to make sure that first disclosure is relatively robust and provides a good reflection of JADE101's profile at both dose levels that have been randomized simultaneously. It will be a very biomarker-rich initial disclosure, including the IgA and pathogenic IgA reductions, which gives you a high conviction that you will translate into longer-term clinical benefit given the consistency which pathogenic IgA depletion has resulted in large reductions in proteinuria and eGFR stabilization.

We haven't really defined yet what that minimum dataset is necessary for that first disclosure, but it will be biomarker-rich and include the important clinical endpoints of UPCR and eGFR as well as, obviously, the safety moving into IgAN patients. So look forward to that first disclosure next year.

Our next question comes from the line of Matt Phipps with William Blair.

Congrats on great data and execution here. I guess how confident are you in the ability of this profile from healthy volunteers to be maintained across a wider distribution of patient body weights given severe does seem to struggle in higher body weight patients. And then it was kind of asked, but if both doses are successful in the Phase III and show similar profiles based on your modeling of IgA reduction, would you seek approval of both doses to give physicians some flexibility in case maybe they have patients with higher body weight or higher baseline proteinuria?

Thanks, Matt. Yes, maybe I'll take the second question first and then pass it to Andrew to talk about the modeling and how we have confidence across the population in IgAN with JADE101. Yes, we are taking the Q12 weeks forward and believe that that's the dose that will provide the levels of IgA reduction required for robust proteinuria lowering and then stabilization of eGFR.

And frankly, if that data continues to look as we expect, that will be the dose that we aim to commercialize and to as well just put in the label and the Q8 potentially will not be necessary. But we do anticipate potentially that there could be a scenario where some physicians may want to intensify dosing in some patients. But we really do need to see how the data plays out to understand is there any additional benefit from intensifying the dose down to that Q8.

Right now, as you saw and Andrew walked through the modeling, it's not clear there will be more efficacy based on that intensification just because we are really maximizing the IgA reductions based on that Q12 weekly dose. But in our interactions with the steering committee and KOLs when we talk through the dose design, they do like that we are testing this and really understanding what is that dose exposure response and how does that translate to clinical activity.

Because with JADE101, we're actually quite -- in a quite unique position where we can test that -- that has not been done with other agents. But because of the profile of the drug, we can really understand what is driving activity IgAN. Andrew, do you want to talk a little bit about the modeling across body weights and expectations there?

Yes, happy to. Thanks for the question, Matt. We do think the point you raised around sibeprenlimab at the population level do leave an opportunity for JADE101 to capture more of the full efficacy available across the population for the anti-APRIL MoA, patients with the higher body weight half in the Phase III study had about 10 or so percent less proteinuria reduction than the leaner half of that Phase III population, suggesting the potential for an agent that addresses the population at a whole more effectively.

The way we built these pharmacodynamic models was really using the sibeprenlimab exposure response as a foundation, both for the APRIL-mediated IgA reductions, but also to establish what a virtual IgAN patient population looks like for the clinical trial simulations we ultimately captured. So the IgAN population variability is built into these pharmacodynamic models. And as we showed, the 350-milligram dose doesn't just do really well at maintaining IgA reductions in that 70%-ish range for the mean or median patient, but does it very well at the population level. So we do feel confident based on these simulations that we have the potential to more broadly impact the patient population as a whole to optimize the efficacy available to anti-APRIL.

Our next question comes from the line of Rami Katkhuda with LifeSci Capital.

Just wanted to pass along my congratulations on the data as well. Two quick ones for me. First, can you touch on whether you expect there to be any safety implications associated with the more rapid and deep IgA reductions observed with JADE101? And then given the reductions across IgM and IgE as well, do you expect to pursue JADE101 in additional indications?

Thanks, Rami. I think the short answer to the first question is no. We don't anticipate any safety concerns with rapid and robust IgA depletion. We have seen across this mechanism now with 4 other agents selective APRIL or the APRIL/BAFF really robust lowering in IgA, especially with the selective anti-APRIL that does not increase risk of infection, and it seems to be very, very safe and well tolerated.

Also, we're very reassured by the fact that the IgG levels are not going down below 3 grams per liter. And so I haven't seen any cases of hypogammaglobulinemia. So we feel really confident about with this mechanism that it's going to be safe and well tolerated. Yes, really good call out on the IgM and IgE. IgM, we definitely feel like there are life cycle opportunities here. There are a number of IgM-mediated diseases that we are looking into. Of note is one called multifocal motor neuropathy, which is a drug that -- or an indication where several companies are testing complement inhibitors. We think that going upstream and targeting IgM, which is the pathogenic driver of the disease could be very beneficial for patients. So we're looking at potentially looking at a signal-seeking trial in MMN.

There's also anti-MAG neuropathy and cold agglutinin diseases, which are all IgM-mediated diseases. IgE, we're still looking at it and trying to understand what would be the value in terms of IgE-mediated diseases, but very intriguing finding that there are good reductions in IgE. So we will think about what can we do with that. Just to note as well, the other potential life cycle opportunity that we have on our radar and Otsuka has started a Phase II trial with sibeprenlimab in sjogren's, and they're anticipating reading out that data around the middle of next year. So we'll really be looking for that data understanding should we move quickly into that indication as well. So lots of really good potential life cycle opportunities for JADE101.

Our next question comes from the line of Vamil Divan with Guggenheim Partners.

Congrats again on the data. So maybe a couple of just clarification things from a question I'm getting from investors here. One on the ADAs, I know you're saying there's no apparent impact on the PK/PD, but can you provide the percentage of patients that had ADAs in the trial?

And then second one is around the URIs that you mentioned. I think you said the rates were slightly lower in patients who got JADE101 as posed to placebo, but maybe you can just clarify or provide any more details on those cases.

And finally, my question was actually around just the presentation of the product, especially with this the 700 milligram loading dose, whatever you can share in terms of the Phase II, the Phase III, how you plan to present the product, it will be a prefilled syringe, an auto-injector and also comment sort of commercially how you're thinking about that? And would the loading dose be something you expect to be given by a health care provider? Or would that also be done just by the patient?

Yes. Thanks, Vamil. Maybe I'll take that last question about the presentation of the product and then Andrew, you can talk about respiratory tract infections and [ AEs ]. Yes, our goal is to make JADE101 as convenient as possible for patients. So the goal is at-home administration for the induction doses as well as the maintenance doses. So we are setting up our patent development pathway to enable that potentially. Right now, we do just have a liquid and vial format for the formulation. We are looking at a prefilled syringe and an auto-injector, and we're working out the development pathway. But the plan is at launch to have a very convenient device that is really suitable for patients to inject at home. Andrew, do you want to take the question on infections and ADA?

Yes. Thanks, Tom. So yes, just to clarify, upper respiratory tract infections were generically slightly lower in the JADE101 group relative to the placebo. So encouraged by that, consistent with the class that long-term anti-APRIL has not shown broad immunosuppressive effect, including on upper respiratory tract infections.

On the ADA, we haven't disclosed rates for this ongoing study, but really encouraged by the lack of any impact of ADAs on PK and PD. We've seen nothing in the profile to date that provides us any concern around repeat dosing in IgA nephropathy patients. And as I mentioned, by design, JADE101 was intentionally designed to reduce the risk of immunogenicity as a fully human IgG1 as well as that novel epitope to avoid large immune complex formation. And we do think that's playing out in an encouraging way in the immunogenicity profile in Phase I. We'll continue to follow, obviously, with repeat dosing in IgAN patients, but nothing of concern.

Our next question comes from the line of Arthur He with H.C. Wainwright.

Congrats. So just one question from my side. So I just noticed that if we look at the drug 101 concentration as well as IgA reduction within the intended dosing interval, the variability for those two concentration is very tight. So Andrew, maybe can you speak to these -- how this can differentiate 101 from the sibe and the pove in terms of the efficacy-wise?

Yes. Thanks, Arthur. So we have been able to use the exposure response that you highlighted there for JADE101 plasma concentrations versus IgA reductions over time. You do this using indirect response modeling since the IgA reduction is not a direct result of the PK, but secondary to APRIL suppression. And what we're really excited by is the remarkable in vivo IgA lowering potency of JADE101. You can calculate using those analyses an in vivo EC50 of about 10 picomolar. So you really require very little JADE101 to get these deep and sustained reductions in IgA. And we think that's really the property that's manifesting in these more rapid and deeper IgA reductions than observed with those first-generation agents, including povetacicept and sibeprenlimab. So I do think this differentiated potency profile is really key for us to be able to achieve this potentially best-in-class profile with the potential for faster, deeper and sustained IgA reductions, hopefully translating into better clinical activity.

Our next question comes from the line of Kaveri Pulman with Clear Street.

Congrats on the excellent results. Maybe just a couple regarding the faster onset of IgA reduction, how much of this you believe is due to higher affinity versus higher dose? And how much benefit faster onset can provide? How meaningful or important it is to physicians? And with the healthy volunteer data and the overall IgA reduction, which I understand correlates well with patients overall IgA reductions. But what read-through it provides to actual reduction in Gd-IgA1 levels and autoantibodies that patients develop? And how much of that reduction specifically correlates with patient benefit?

Thanks, Kaveri. Yes. So on the IgA, total IgA to Gd-IgA, we have seen historically that they translate very, very closely, the correlation is extremely high, and it's pretty much a 1:1. Correct me if I'm wrong on that one, Andrew.

No, that's correct. At ASN last year, we provided our analysis of all of the publicly available data and a very strong association between total IgA and Gd-IgA1. So we do feel like total IgA provides the full information available.

Yes. And then you asked how clinicians would see this faster onset. -- physicians definitely like the goal is to control kidney function over the long term. So they haven't said, oh, I want an agent that acts within the first couple of months. But what we do know is it does take a significant amount of time for the other agents to reach their peak reductions of IgA and their peak reductions of proteinuria. And if a clinician is, in fact, waiting 9 to 12 months to understand the full effect of the medication and if it's really providing that benefit hitting those proteinuria goals like below 0.5 grams a day or below 0.3, we do know that something that does have an earlier onset really will help them understand like how is the medication performing.

We also think that from a comparative point of view, looking at those 9-month interim analysis of proteinuria, if we can capture more of the efficacy, that's available to the mechanism at an earlier time point, then that will compare very favorably when clinicians are assessing which medication to use based off of those initial 9-month proteinuria analysis. We could look quite good in comparison. Andrew, do you want to take the question on faster onset? Is it driven by the affinity or the dose?

Yes. We do think that rapid onset of IgA reduction is driven by the ultra-high binding affinity to really potently and quickly fully inhibit APRIL. We see this when we look at the free APRIL profiles. Remarkably, following a subcutaneous dose of JADE101, you can get full systemic APRIL suppression below the limit of quantification within 2 hours of that dose. So it really does show a very potent APRIL suppression at very low concentrations of JADE101, which triggers the very early and rapid IgA reduction.

That concludes the question-and-answer period. I'll now turn it back to CEO, Tom Frohlich.

Thank you. On behalf of the Jade Biosciences team, thank you for joining us today. A replay of this webcast will be available on our website. If you have any further questions, feel free to reach out to our Investor Relations team at [email protected].

This concludes today's conference. Thank you for your participation. You may now disconnect.

Good morning, everybody, and welcome to another presentation with the Oppenheimer Life Sciences Conference. I'm Trevor Allred, an analyst here with the Oppenheimer Life Sciences team. We have with us today Tom Frohlich, CEO at Jade Bio. Tom, please take it away.

Great. Thanks, Trevor. Much appreciated, and thanks to the Oppenheimer organization for hosting us. It's been a really great conference. And I'm very pleased to provide an overview of Jade Biosciences on behalf of our team.

As always, I'll be making forward-looking statements. So for more details, please do look at our SEC filings.

Jade Biosciences is a company really dedicated to developing best-in-class therapeutics across a number of different autoimmune diseases. We have been established with three programs that we have had access to from Paragon. Paragon Therapeutics is a company based out of Boston who are very talented protein engineers. They have a real knack for developing very high affinity binding monoclonal antibodies, but then also have deep expertise in half-life extension technology. So we've applied that strategy across our three programs really to develop best-in-class therapeutics against validated programs, validated targets.

What we believe the benefits of using that high affinity binding concept along with half-life extension technology really provides two key benefits. One is more complete inhibition of the target throughout the entire dosing interval to really maximize clinical activity available to the mechanism. And then the second one is, of course, with this long extended dosing interval really to minimize patient burden and have the most convenient medicines available for those patients.

So our lead program is JADE101. It's an anti-APRIL initially in development for IgA nephropathy, a large and exciting opportunity with a rare kidney disease that has increasing focus on it recently with new approvals in the area. With JADE101, we believe we have the opportunity to become the best-in-class and potentially best-in-disease molecule and capture a large portion of that large and growing opportunity.

We're currently in a Phase I healthy volunteer trial, which is aimed to read out in the first half of this year. And that readout is crucially important to us and a very big milestone for the company, because we're quite lucky in IgA nephropathy. It's a very biomarker-rich disease. And the readouts that we see in the healthy volunteer population are a direct read-through and very predictive to the clinical activity we expect to see in patients. So with that data in the first half of this year, we'll be able to have an extensive characterization of the compound, really understand the profile, what level of clinical activity we can anticipate as well as the dose interval to be able to move very quickly with high conviction into patient trials and move very rapidly towards marketing authorization. We did disclose earlier this year and we plan to initiate a Phase II in the middle of 2026 with interim data in '27. So very exciting time for that program.

Our second program is JADE201. Similarly, very exciting. It's an anti-BAFF-R, which is following the footsteps of ianalumab, which is their BAFF-R at Novartis, which is currently across 6 different Phase IIIs. So has very broad potential across a number of different autoimmune diseases. We are moving that program forward quickly with a planned first-in-human to initiate in the second quarter of this year with data in 2027. So our second program and moving Jade towards being a multiple clinical asset stage company.

We have a third program, JADE301, which we have not disclosed the target for competitive reasons. We will disclose that as we get closer to the clinic, which is planned for the first half of 2027. Follows a similar playbook where there's a more advanced asset that has derisked the target, but we believe through our protein engineer capabilities from our partners at Paragon, we can develop a best-in-disease molecule. So stay tuned for that. We will disclose more on that as we get closer to the clinic with that program. We didn't nominate a development candidate on that. We've previously disclosed that.

This is all supported by a very strong team with very good capabilities in IgA nephropathy and the other areas that we're going into, a proven track record of success there and all underpinned with a strong financial position. We closed 2025 with $336 million in cash, which gets us into the first half of 2028, covering these key milestones listed here on the slide.

So JADE101, an extremely exciting molecule for IgA nephropathy. Why are we so excited? Well, there's four key reasons. One, IgAN is going to be a very large commercial opportunity. We had previously estimated that it was around a $10 billion opportunity, a branded market opportunity in the U.S. alone. But we actually believe now that, that's actually probably very conservative and underestimating. We saw the recent approval at the end of 2025 of VOYXACT, which is sibeprenlimab, which is Otsuka's anti-APRIL. And it was approved with a very broad label. So really increasing the population that is suitable for this class of medications. And also, they priced at the top end of the range that people were expecting. So we actually believe this $10 billion opportunity likely is conservative, and we've seen analyst reports that have several fold higher than this. So a large commercial opportunity with room for multiple entrants and a very attractive place to play.

We believe within that large opportunity that the selective anti-APRIL class is really poised to become frontline foundational treatment for all patients diagnosed with IgAN. And that really is because the mechanism is disease-modifying. It has the potential to take away the root cause driver of disease, that pathogenic IgA. It has demonstrated with other agents to have large decreases in proteinuria and to stabilize kidney function. So we really do believe that anti-APRIL class is going to move to frontline and be foundational for all patients with IgAN.

Within the anti-APRIL class, we believe we have a straight shot at becoming the best-in-class agent. Our JADE101 is designed to capture the full efficacy available to the mechanism. It has superior potency. It's femtomolar binder to APRIL, over 750-fold more potent than sibeprenlimab.

Of course, as well, it has the YTE, half-life extension mutation, which does garner a long duration of action, and we believe will be the most convenient medication available for IgAN. We're aiming for a dose interval of no more frequent than one subcutaneous injection every 8 weeks, which we believe for this young patient population will be really crucial and very highly differentiating.

Finally, there is a very efficient path to market. I already mentioned that healthy volunteer biomarker data is very translational and predictive of what we anticipate to see in patient. So that will be very just derisking that data we expect in the first half of this year. But also the surrogate endpoints are used for approval. So things like proteinuria and eGFR can be used for a very efficient path to market.

So just elaborating a little bit on the size of the opportunity. I already mentioned that this is a very large opportunity, about 170,000 patients diagnosed in the U.S. alone with several hundred thousand in Europe and several million in Asia. We believe about 60% to 75% of those patients are eligible for treatment with an anti-APRIL medication. And that's really driven by their risk of disease progression. You can see in the Kaplan-Meier graph on the left, the lifetime risk of progression in all patients with IgA nephropathy is high over their lifetime. Patients are typically diagnosed in their 20s and 30s and do remain at high risk of kidney function loss or death.

And this has largely calculated the risk of progression by their proteinuria levels, which are directly associated with time to loss of kidney function. And you can see that patients at higher levels of proteinuria really declined quite quickly, over a 50% chance of losing kidney function completely within 5 years if you're above 1.75 grams a day. But conversely, that really drops quite significantly if patients are at lower levels of proteinuria.

Here in the lowest quartile, roughly below 0.5 grams a day, you can see that patients are at the lowest risk of long-term disease progression. And that's really why there's a call with the KDIGO guidelines to really target patients to that below 0.5 grams a day to minimize that risk of long-term kidney function loss. And what you can see here is we believe that it's going to expand the patient population, these new recently published guidelines. Any patient who's above 0.5 grams a day should be diagnosed with a biopsy. And then that's really established as the new target that physicians should treat below, really highlighting the need for very efficacious medications. They've established this proteinuria target that all patients need to get below 0.5 grams a day, but preferably below 0.3 grams a day, which is really clinical remission back into the normal zone. So this is really going to bolster the need for very efficacious proteinuria lowering medications and highlight the use of patients with the highest -- with medications with the highest levels of proteinuria reduction will really drive adoption.

The other thing that's very encouraging for the anti-APRIL class on this slide and the KDIGO guidelines is they're really redefining treatment strategies. Historically, patients were always treated with ACE inhibitors and then steroids if they weren't responding. But now they're really saying that patients need to be on two classes of agents or two types of agents, one that manages local nephron loss, so things like ACE inhibitors, SGLT2s and ERAs. But additionally, the patients should also be on medications that treat IgAN like an autoimmune disease and reduce that pathogenic form of IgA. And we really believe the only classes of agents that have shown this dramatic reductions in pathogenic IgA are the selective anti-APRILs or the APRIL/BAFF. And we strongly believe there is going to be a preference for the selective anti-APRILs over time.

So JADE101 is very well positioned to capture a large portion of this IgAN market. The femtomolar potency and half-life extension really confer properties that are going to make it best-in-class potentially. It will have that opportunity to fully suppress APRIL through the dosing period to really capture that full efficacy available to the mechanism, so potentially best-in-class efficacy, do that with minimizing treatment burden. So no more than one subcutaneous injection every 8 weeks or potentially 6 injections a year. And to do that really with the most narrow focus on the targets that are driving pathology and pathogenesis of disease to avoid unnecessary immune suppression. I mentioned in the last slide that we believe that APRIL is providing that disease-modifying impact where the dual APRIL/BAFFs potentially have unnecessary immunomodulation.

And we believe that because really that the biology of the disease points to APRIL as really the key driver in disease. IgAN is a plasma cell disease, where it's caused by an increased production of galactose-deficient IgA, which does result in autoantibodies that form immune complexes that then damage the kidney. It is known that APRIL is really driving plasma cell differentiation and antibody class switching to IgA-producing plasma cells that's really driving this and hitting APRIL has been shown time and time again to really ameliorate disease.

Conversely, it's not quite as clear the role that BAFF inhibition is playing in IgAN. It has been shown or tried with rituximab, CD20 has been used in IgAN patients with really no impact on IgA, IgA autoantibody production or proteinuria with no impact on eGFR. Similarly, a selective anti-BAFF inhibitor, blisibimod was used and similarly had no impact on IgA or proteinuria.

And we've seen that play out as well in the clinical studies as well. This is a slide showing the recent results with sibeprenlimab from their Phase III. So sibeprenlimab is a selective anti-APRIL, and it also shows the results published by atacicept. Both showing very good reductions in proteinuria. And a reminder, atacicept is the dual APRIL/BAFF. Very good results in proteinuria. But you can see that the results are actually quite similar. And it's clear here, there's not an increased effect of adding BAFF on top of the selective anti-APRIL inhibition, really driving home that point that APRIL is driving efficacy in this class. And we believe for that reason, we will be really preferred by physicians to not have long-term immunosuppression but is not driving clinical activity.

So within the APRIL class, why do we think that we have the opportunity to be best-in-class. As I mentioned, sibeprenlimab was recently approved. But with their commercial presentation, we don't believe they're fully capturing the efficacy available to the mechanism. They did switch from an IV body weight adjusted presentation in Phase II to a flat, more convenient subcu presentation in Phase III, where they aren't capturing the full efficacy. You can see here in the Phase II study on the right-hand side that they did test 3 IV body weight adjusted doses, 2, 4 and 8 milligrams, where they did see a clear dose-dependent reduction in APRIL, in total UPCR reduction and very importantly, getting more patients at the high dose up to patients into complete remission. So nearly twice as many patients below 0.3 grams a day.

Their commercial presentation, which is the 400 milligrams is roughly similar to their middle dose here, the 4 mg per kg. So we believe they're leaving some efficacy on the table that we aim to capture with JADE101.

So why do we believe we can capture that? Well, JADE is really designed from a de novo antibody screen to be ultra-high binding. And as I mentioned, it's femtomolar potency over 750-fold more potent than sibeprenlimab and over 2,000-fold more potent than zigakibart. It also has the YTE half-life modification to really allow for extended dosing, complete coverage of APRIL through the dosing period, but then also this really more convenient, fewer injections for patients.

This was exhibited in the NHP profile. On the left-hand side here, you can see that increased potency and half-life extension do translate into extended PK with JADE101 compared to sibeprenlimab in the purple. And you can see here nearly a fourfold improvement in half-life of JADE101 versus sibeprenlimab.

On the right-hand side in NHPs, you can see that, that does translate into pharmacodynamic activity as well. With in purple, you see sibeprenlimab have a very typical reduction in IgA with a rebound post, around the 3- or 4-week period, whereas with JADE101, you do get these deep and prolonged reductions in IgA, really giving us that confidence that JADE101 has the potential to extend that dose interval and really capture the full efficacy that is available to this mechanism.

So we should know in the first half of this year in healthy volunteers if we are achieving that. We did initiate the study in 2025. It's a 4-cohort dose Phase I trial, where we are measuring safety and tolerability. We, of course, will look at PK immunogenicity. But most importantly, we are looking very closely at pharmacodynamics, things like reduction in APRIL, reductions in IgA. And this is particularly important to us because we have built a translational framework where we have looked at the impact of APRIL and IgA neutralization across all the trials that have been done with both the selective anti-APRILs and the dual APRIL/BAFFs and figured out how to translate that into what we anticipate seeing in patients and really do observe that it's very, very highly predictive.

So with this data that we'll be generating in the first half of this year, we will be able to understand, are we hitting that clinical profile? Where we do have these large drops in IgA supported by reductions in APRIL. And we'll be able to see how does that compare to the clinical doses of the other agents that are on the market. Are we hitting that profile of that top dose of sibeprenlimab IV? And are we able to do that for an extended period of time to really pick our dose and our dose interval to move forward into patient trials.

And we'll have confidence and conviction around that because there is really strong evidence showing that healthy volunteer reductions in IgA are very closely correlated to what you expect to see in IgAN and that those IgA reductions do correlate as well with UPCR clinical activity. So really giving us that conviction to move forward as quickly as we can. And as mentioned, we are doing start-up activities at risk right now to initiate a Phase II around the middle of this year.

So just really in summary, we do believe that JADE101 has that possibility of being a best-in-disease agent for IgA nephropathy. With a high potency, we can capture that clinical activity available to the mechanism and do that with a very favorable Q 8-week single injection or less. So a very exciting time for us and very meaningful period for the company as we move towards this data readout.

So switching gears quickly to JADE201. This is an anti-BAFF monoclonal antibody that is following the footsteps of ianalumab at Novartis. We are very excited by this mechanism because it has broad utility across a number of different autoimmune diseases. And we believe this mechanism, which has been validated by ianalumab, really overcome some of the limitations with other B cell reducing agents. It's been long established that deeper B cell depletion does translate into better clinical activity in these autoimmune diseases. And with the BAFF-R mechanism that has that dual mechanism of action, we can overcome some of these key elements, obviously, getting more complete B-cell depletion and hitting broader set of cells.

But also with things like CD19 and CD20, when you do deplete B cells, you actually get this compensatory increase in BAFF, which is a pro survival signal, which actually drives quick repopulation. Also, with those mechanisms, the CD19s and CD20s, they can only kill B cells in the presence of effector function cells. So they get deep B cell depletion in circulation, but have trouble getting at lymphoid tissues.

And what we can see with JADE's dual mechanism of action, you do have this direct cytotoxicity similar to CD19 and CD20. So this rapid B cell depletion in circulation. But you also get this blocking of the B cell signaling by blocking the BAFF receptor. And what that ends up doing is you prevent that B cell repopulation through the upregulation of BAFF, but also you can get B cell starvation in areas where there are not effector function cells. So really seeing better tissue B cell depletion.

So JADE201 is designed to mimic the pharmacological activity of ianalumab, but to do it with a half-life extended antibody. And our preclinical data really does show that we are getting that dual mechanism. So we are blocking BAFF signaling in cells and also getting this direct cytotoxic activity in circulation.

This is just a quick NHP study showing that we do have this extended PK, are blocking BAFF-R occupancy and do get deep and prolonged B cell depletion in nonhuman primates. And of course, importantly, the limitation that we're trying to overcome with ianalumab is that it has a very short human half-life of 10 days, only 2.5 days roughly, 2.7 days in nonhuman primates. And you can see that with JADE201, we do have a meaningful improvement over that half-life.

So what we are doing in -- our study is we are beginning that trial. We anticipate having it started in Q2 of this year. It will be a study in rheumatoid arthritis patients. But think of that study more as a healthy volunteer surrogate, because we can't go into healthy volunteers with this mechanism. And we do anticipate having data on that study in 2027. We will be looking at safety and tolerability, looking at PK, of course, the pharmacodynamics, looking at B cell depletion dynamics as well as some flicker of efficacy in RA patients with the joint and swollen -- sorry, tender and swollen joint counts to measure DAS28 to understand if we are getting a small signal. But caveat there that the study really isn't powered around efficacy. So it's more around the safety and the pharmacodynamics.

Now we like rheumatoid arthritis as a potential indication. About 5% to 10% of patients with RA end up on rituximab. So there is an opportunity, but it is unlikely to become one of our lead indications for 201. We are currently evaluating actually over 20 different indications where rituximab is standard of care or highly used. And looking at two different strategies. One is to look at the indications that have this asterisks that are where ianalumab is currently in a Phase III study and understand the fast follower population or fast follower indications. And we are also looking at a number of different indications where rituximab is used, where Novartis likely didn't go for strategic or pipeline prioritization reasons. And so as our data unfolds and we see more information from ianalumab, we'll be able to make that determination and disclose our lead indication.

So just in summary, very quickly wrapping up. It's a very exciting time for Jade. We are moving with the anti-APRIL program, JADE101, to very meaningful data in the first half of this year, initiating a Phase II in the middle of this year with data on that in 2027 and then advancing our second program into the clinic and then driving towards having three clinical programs in the clinic by the first half of next year. So a very exciting time, and thank you for your attention.

Great. Thanks, Tom. Very comprehensive overview. Looks like it's going to be an exciting time to be taking a look at Jade. So thank you all for joining us, and we'll see you in the next presentation.

Great. Thanks for having me.

Good morning, everyone. I hope everyone's had a good conference week. Welcome to the 44th Annual JPMorgan Healthcare Conference. My name is Cliff Zhang, a member of the Healthcare Investment Banking team based in New York. Our next presenting company is Jade Biosciences. And speaking on behalf of the company, I'm pleased to welcome CEO, Tom Frohlich. Please give it up for Tom.

Thanks, Cliff. It really -- it's a pleasure to be here. Thanks for hosting us at the conference. I'm really pleased to provide an overview of Jade on behalf of the team. Very exciting time for us as the company. So pleased to provide an overview. I will be making forward-looking statements. So if you have more request for information, please contact or please read our SEC filings. So Jade Biosciences, we're a company that is really dedicated to developing best-in-class therapeutics for autoimmune disease. We were launched in the middle of 2024, really based on 3 assets that we have access to from a company that we've licensed to and have access to another one from Paragon Therapeutics.

Many of you are probably familiar with Paragon. They're a protein engineering company based out of Boston, have an excellent track record of developing very high-quality monoclonal antibodies, have a particular expertise in developing high-affinity binding antibodies, but also in half-life extension technology. So really, the playbook for our 3 assets is to have best-in-class possibilities to go after targets that have a high degree of clinical validation, but where we do believe we can improve upon that profile through that better binding through the entire dosing interval to potentially have better levels of clinical activity, but then, of course, to have longer duration of action to provide less treatment burden for patients and a therapeutic that's much more convenient.

So our lead program is JADE101. It's an anti-APRIL initially targeting IgA nephropathy, an extremely exciting area. I think it's developing into a much larger market opportunity than most people have previously recognized. We have a strong conviction that the selective anti-APRIL class is going to move to frontline and be foundational therapy.

Now within the selective anti-APRIL class, there are 2 agents that are further ahead of us that has provided that clinical validation, but we do believe there's a straight pathway for us to become the best-in-class and potentially the best-in-disease through that more complete inhibition of APRIL through the entire dosing period to provide that higher level of clinical activity, but of course, that longer dose interval as well to be the most convenient therapy on the market. That agent currently is in Phase I. We completed enrollment last year, and we're currently monitoring the data. And we plan to have that data. We've guided last week that, that data will be disclosed in the first half of this year. Now it is extremely important data for us, not only because it's the first data set for us as a company because -- but because in IgA nephropathy, it's a very biomarker-rich indication where we can see the biomarkers that are reduced in healthy volunteers are actually a direct read-through to the expected clinical activity in patients.

So we will be able to pretty much fully characterize the drug through that healthy volunteer study, give us all the information we need to move extremely quickly into patient trials. And we did actually provide guidance last week that we do plan on dosing our first patient in the Phase II around the middle of this year with data in 2027. So an extremely exciting program. JADE201 is an anti-BAFF receptor really along the lines of B-cell depleters, trying to overcome some of the challenges with agents like rituximab to provide more complete B-cell depletion and actually provide B-cell depletion as well in peripheral tissues to have the higher levels of clinical activity. This agent is actually following in the footsteps of ianalumab, which is a program that's currently at Novartis in 6 different Phase IIIs across a number of different autoimmune indications.

So an agent with very broad potential, but looking to extend the half-life with that agent as well to be able to provide better receptor occupancy coverage through the dosing interval and provide better convenience for patients as well to be highly differentiated. So that program is currently on track to get into a Phase Is in first-in-human study in the second quarter of this year, aiming to have data on that in 2027 as well.

We have a third program as well, which we have not disclosed the target yet for competitive reasons, but follows that similar format where there is a biological validation that's from a product that's further ahead in the clinic, and we aim to have that into the clinic in the first half of 2027. So an extremely exciting profile for us as a company. We have that backed by a very, very solid team. Me and actually Andrew King, who's our Head of R&D, who is going to come up here for Q&A. We both have a background at Chinook Therapeutics. We are both early employees there and really they're through the pipeline build right up to the acquisition by Novartis.

We managed to recruit in what we think is kind of the best elements of that team, and we are driving these programs forward with a very highly capable experienced team, but we're also backed by a strong foundation -- financial foundation, we closed last year with $336 million, which is enough to fund operations across these 3 programs into the first half of 2028.

So a very exciting year ahead where we go from last year -- 2024, starting the company; last year, building the foundations with the pipeline, with the team, the capital structure; and 2026 really looks to be a transitional year for us where we go to having clinical data and then multiple clinical programs as well.

So why are we so excited by JADE101? There's 4 kind of key areas that we're really focusing on for our excitement. The first one is really around the potential market opportunity. As I mentioned, IgAN is probably slightly underappreciated in terms of its size. We believe it's a $10 billion-plus opportunity in the U.S. alone. Although recently, we saw Otsuka get approval with sibeprenlimab in November of last year, and we actually were pleasantly surprised with Otsuka's pricing.

They priced at sort of at the high end of the range of what we were anticipating, so actually, these market estimates are probably low. We've actually seen research analysts with multiples of that $10 billion number. So we think it's a very large commercially attractive opportunity. Within that opportunity, we think that the selective anti-APRIL class is going to move to frontline and be foundational therapy for all patients at risk of progression with IgAN. And that's really because they have this ability to reduce pathogenic IgA, which is that driving factor to be disease-modifying.

They've demonstrated large reductions in proteinuria and stabilization of kidney function, doing that with a very safe tolerability profile. With JADE101, though, we think we can be the best-in-class to use the qualities of our antibody to have superior potency and that long half-life to really provide the best clinical profile and have the best dosing interval that will be most convenient for these patients.

And then as I mentioned, there's a very efficient development pathway where we can see biomarkers in that healthy volunteer data that is hugely derisking for the program because we can really see what the clinical profile will look like, and also give us our dose and dose interval and allow us to move extremely quickly into patient trials.

So I won't spend too much time on the market other than to say we do think it's a very large market. There's about 170,000 patients in the U.S., several hundred thousand in Europe and several million in Asia. We do believe that 60% to 75% of those patients do require treatment and are eligible for the selective anti-APRIL class. And we choose that 60% to 75% range because those are the percent of patients we believe are over 0.5 gram of proteinuria a day. So those are the ones that are more at risk of disease progression.

As you can see on the left -- right-hand side of this chart, if you look at epidemiological studies of patients over time, those that are at high proteinuria levels per day do end up having rapid loss of kidney function. So it really is the goal of therapy to get patients as low as possible to minimize that long-term risk of progression. You can see those in the lowest quartile below roughly 0.5 gram a day are the ones that have the minimum chance of disease progression over time. And the recent KDIGO guidelines really do spell that out in a lot more detail, the importance of this proteinuria target of less than 0.5 gram a day.

There's 3 key elements there. One, they believe that any patient who is above 0.5 gram a day that is suspective of IgAN needs to get a biopsy to really be diagnosed. So we believe that's going to expand the patient population, but anybody who's not below that target of 0.5 grams a day needs to have further therapy or more therapy added.

So we think this really strict aggressive proteinuria target, it's really going to highlight the need for highly effective therapies to come to the market, and it's going to be a key selection factor for physicians when they're deciding what therapy to initiate for their patients.

The other element that we think is a good tailwind for the class is that the KDIGO guidelines have actually also recently really called out specifically with the availability of these new agents that IgAN needs to be treated like an autoimmune disease, and that every patient needs to be on a therapy that has proven to reduce pathogenic IgA. So we think that's another big tailwind for that anti-APRIL task that will help support them move to frontline therapy.

The only two classes of agents that are in later-stage development that have consistently shown these reductions in pathogenic IgA are really the selective anti-APRIL class or the dual APRIL BAF. And we have a strong belief that the efficacy from those classes of agents is primarily driven by APRIL, and there's going to be a preference to select those drugs that are really selected anti-APRILs because BAFF is not contributing significantly to the efficacy of these agents.

And we know that -- we believe that because of the pathology of IgA nephropathy. If you look at the right-hand side of this slide, you can see that APRIL really is a plasma cell-mediated disease, where the plasma cell is driving production of galactose-deficient IgA, then that's recognized as foreign. There's an autoantibody. You get these immune complexes that form and then deposit in the kidney to create injury.

And we've seen that with broad B-cell depletion, which targets cells -- B cells outside the plasma cells, so things like rituximab, there's actually no impact on IgA levels. There's no impact on proteinuria. And similarly, with specific BAFF neutralization with an agent called llacitimod, which is a selective anti-BAFF inhibitor, it was tried in IgA nephropathy, with actually no effect, did not reduce IgA, or did not reduce proteinuria. So the flip side of that is anti-APRIL neutralizing agents have consistently shown reductions in proteinuria, shown reductions in pathogenic IgA, and in fact, have even demonstrated early kidney function stabilization as well.

So we strongly believe that selective anti-APRIL therapies are going to emerge as the preferred class. There's recent also Phase III data that has looked at selective anti-APRIL, so ociperlimab on the left-hand side of this graph versus atacicept, which is a dual APRIL BAFF. And you can really see that there's not a significant difference, or there isn't a big additive effect of blocking BAFF.

So we believe in the presence of this data where you don't get additional clinical activity, but you have broader immunomodulation with the BAFF that the preference is going to be for the selective anti-APRIL therapies.

So why do we believe that there's room for us within the anti-APRIL therapies? We really believe there's a possibility to differentiate on 2 options or 2 areas. One, where I mentioned longer duration of action, so a better dosing interval. But the second one is we don't believe the therapies currently in development are optimizing dosing. This is the Phase II study from Otsuka's sibeprenlimab, where they used IV body weight-adjusted dosing across 3 different dose levels. And you can see that at the lower dose at the top here, that they're not completely inhibiting APRIL, and they're only actually getting complete inhibition of APRIL across the dosing interval at the top 8 mg per kg dose. And that was associated with higher levels of overall proteinuria reduction and actually getting more patients into that target zone of below 0.3 grams a day, so back into the clinical remission zone.

But Otsuka actually switched from IV dosing to a flat subcu in Phase III, which is great for patients because it's much more convenience and convenience is really going to drive uptake in this young patient population. And when they switch to their subcu dose, they really chose a dose that's kind of approximating their middle dose, so around that 4 mg per kg dose.

So we believe that they're leaving some efficacy on the table that we can capture with our agent. So what is JADE101, and why do we have a strong conviction, we can capture that efficacy? Well, it's designed from a de novo screening campaign, and it has ultra-high APRIL binding affinity. In fact, it's in the femtomolar range, which is 750-fold more potent than sibeprenlimab. It's also half-life extended. So it does have that extended pharmacology, which we believe will allow us to capture that full efficacy, but also have a long dosing interval for patients.

And the NHP data really supports our thesis. You can see on the left-hand side here, looking at the PK curves in nonhuman primates of sibeprenlimab versus JADE101. Sibeprenlimab is in the purple. You can see a typical PK clearance that you would expect with a monoclonal antibody, but with JADE101 having nearly fourfold longer NHP half-life, so 27 versus 7 days with sibeprenlimab and that higher binding affinity really has much slower clearance and maintains higher plasma exposures for a much longer period of time.

On the right-hand side, that's associated with pharmacodynamics as well. We're very fortunate in IgA nephropathy that we have great PD markers even in NHPs in healthy volunteers. So we can look at drop in IgA, which is very closely correlated to galactose-deficient IgA drops. And you can see a typical clearance curve with sibeprenlimab where you get a very good drop initially, but then as the drug is cleared, you get a rapid rebound, but with JADE101, we actually get deep and durable suppression of IgA over time.

So we are in a Phase I, as I mentioned. We are looking at typical endpoints like safety and tolerability. We think tolerability is very important here. So we will be reporting out things like injection site reactions to make sure it's extremely convenient for patients and be well tolerated, but as I mentioned, the key really is to look at the depth and duration of APRIL and the drop in IgA.

And from that, we'll be able to really understand and fully characterize the drug and understand are we hitting that profile of that top dose of sibeprenlimab IV that they can achieve with a single subcu injection. And we've got conviction around that because Andrew and his team have created this translational framework to look at what effect did all the APRIL and APRIL BAFF antibodies have in healthy volunteers, and we can model that out and predict exactly what we anticipate seeing in patients and how that will impact proteinuria and hopefully, kidney function stabilization as well.

So as mentioned, this will give us all the information for the dose and dose interval to be able to move forward really quickly into patients. And this is just a chart showing that work, it's very closely correlated what you see in healthy volunteers in terms of IgA reduction to patients that translational framework has held, and then also those IgA reductions, how they're associated with proteinuria. So giving us really that strong conviction of this healthy volunteer data.

And finally, just this is a slide to kind of reinforce a little bit about the importance of convenience within this patient population. I don't think I've mentioned yet, but IgAN patients are typically diagnosed relatively young. They're diagnosed in their 20s and 30s. Typically, they're asymptomatic, and they also require decades and decades of treatment. So we think this profile that we're aiming for, which is kind of maximal efficacy available to the APRIL mechanism with infrequent dosing where we think Q8-week dosing is achievable, so roughly 6 injections a year.

We believe that, that will be really preferred by patients and give us the opportunity to gain significant share within this very relatively large indication. So I see I only have a couple of minutes left for the Q&A. So I'll go through JADE201 quite quickly. We are very excited by this mechanism. It's only actually a few quarters behind where we were with JADE101. So it is coming along quite quickly. And as I mentioned, this is an afucosylated anti-BAFF-R monoclonal antibody that's really designed to overcome some of the limitations with previous autoimmune targets.

Things like rituximab, so CD20 and CD19 do a relatively good job at getting B-cell depletion initially, but we know that deeper B-cell depletion is always associated with better clinical activity. And some of the limitations of things like rituximab is when you have rapid B cell depletion, you actually end up getting upregulation compensatory effect of increased BAFF because it's a pro-survival signal and it drives repopulation.

So the aim with our agent is to have this dual mechanism of action where you can overcome that where you do have the same enhanced effector function. So for that rapid B-cell depletion in circulation, but then you're also inhibiting that BAFF signaling by blocking the BAFF receptor and preventing that repopulation. And that has a couple of benefits, one is you're preventing repopulation in circulation, but also you're starving the B cells that are in tissue that might be in areas where you don't have those effector function cells like NK cells to do that killing, so you can also potentially get tissue depletion, which is extremely important in a lot of indications.

So we've designed JADE201. As I mentioned before, we're following in the footsteps of ianalumab, which is at Novartis. So we've designed it to really retain similar pharmacology to ianalumab in terms of its ADCC activity and blocking that BAFF signaling, but overcoming the limitation by introducing a half-life mutation to provide that extended receptor occupancy and also allowing for better injection frequency.

I won't run through all the data, but just to say we're getting good BAFF-R blocking and ADCC activity. In NHP, we have shown very good B-cell depletion, and we are on track to initiate our first-in-human study in the second quarter of this year -- in the second quarter of this year, where we will be looking at safety tolerability. We are initiating this trial in rheumatoid arthritis patients. Think of that more like a healthy volunteer surrogate, because with B-cell depleters, it's not ethical to go straight into healthy volunteers.

In RA patients, you can recruit them fairly quickly. We will be able to look at safety tolerability, look at PK, but also understand the dynamics of B-cell depletion. And also, we'll be able to get some glimmer of a signal on efficacy because we will be measuring swollen joints and tender joints to get a DAS28 score, but it's not really powered for efficacy, but we will get some signal there.

With rheumatoid arthritis, it's a great indication for the study, and we are potentially excited by the opportunity there. In RA, about 15% of patients do end up on rituximab if they fail TNFs and IL-6s and JAKs. So there is a significant market opportunity there, but it's unlikely to rise to our lead indication. It is probably within our life cycle management strategy, but when we think about indications here, you can really think about any indication where rituximab is standard of care or has clinical activity. So we will be looking at a number of different areas and really trying to understand where we can provide the best benefit.

There's 2 strategies here. One is really look at the areas where ianalumab is in later-stage trials. As I mentioned, there are 6 Phase III trials. So we will see more data on those over the next period of time while our trial reads out, so we can really understand where can we rapidly differentiate from ianalumab, but there's also a number of indications where Novartis has not gone, probably for strategic or portfolio prioritization reasons where we could be a potential first-in-class, but a very large market opportunity for this BAFF-R program, so very excited.

So I'll close there, just to say we're extremely excited with where we are in terms of our progress as a young company. I felt like we've -- last year, we've built that foundation with the team, the capital structure, got the pipeline mature to a level where we're extremely excited, and this next year is going to be an excellent opportunity for growth for us with this really crucial readout with the healthy volunteer study for JADE101, where we will be able to characterize very fully that the drug and give us the conviction to move forward really quickly, understand if we're having that profile where we're maximizing the clinical activity available to APRIL with a long duration of action, Q8 weeks or more if we get good data and move forward into later-stage trials.

So thank you very much. Looking forward to a big year of growth for Jade.

Thank you, Tom. So we'll now transition to the Q&A session. We're going to be joined by Chief Scientific Officer, Dr. Andrew King. We've had a number of questions coming from the online audience, so we'll go through those and turn to the audience at the end if time permits. So these are questions regarding JADE101. Can you please elaborate on the bar for success for the upcoming healthy volunteer readout?

Andrew, you built that translational framework. So why don't you comment?

Yes. Although this is a healthy volunteer study, it is going to be a very detailed characterization of JADE101 and highly informative of the future development. What we're hoping to see for success is a favorable safety and tolerability profile consistent with what we've seen with the anti-APRIL mechanism of action. We would like to see a relatively minimal immunogenicity that's going to become increasingly important given what we've seen from sibeprenlimab with 34% ADA positivity in their Phase III study, having a significant impact on PK exposures.

But the real informative information from this study is the biomarker-rich response to the anti-APRIL mechanism. Their analysis has shown that the responses are highly consistent in healthy volunteers as we will see in IgAN patients, and ultimately, these biomarker responses are predictive of disease-modifying clinical activity.

So what we hope to see is an extended PK profile that provides deep and durable deletion of -- depletion of APRIL so a direct measure of target neutralization and the accompanying IgA response that we see with this anti-APRIL MOA, which is sustained for at least 8 weeks, which will provide us confidence we can deliver the full disease-modifying efficacy of the anti-APRIL mechanism and do it with a convenient infrequent subcu dosing schedule of no more often than every 8 weeks.

As a quick follow-up, can you maybe elaborate on the importance of the dosing interval in this patient population?

Yes. We think this is like really critical, and we're seeing convenience drive more and more of some of the choice drivers for clinicians and patients. As I mentioned, patients are typically diagnosed in their 20s or 30s. So they're young, they're healthy. They have outside of -- they don't have comorbidities outside of their kidney disease. They're asymptomatic, which we know asymptomatic diseases are always tougher for compliance. So having something that's as convenient as possible is really important.

And these are people that have like probably busy jobs are taking care of kids and parents. So we think having something that's not that often to dose, you don't have to think about your disease is going to be really meaningful. As Andrew mentioned, our target profile is Q8 week dosing, so 6 injections a year. We've done some small market research with clinicians show the profiles of some of the competitors are Q weekly, some are Q4 weeks. And then we looked at Q8 weeks and potentially some longer dose intervals. And we found that really the big inflection point where you get significant share is when you go from that Q4 to that Q8-week dose. And we think that will be like a really meaningful choice driver to really get preferential share for JADE101.

Another quick question. So maybe how quickly do you think that JADE can move to the registrational study?

Yes. As I mentioned, we feel like we can select the dose and the dose interval for JADE101 from this healthy volunteer data set that we'll report out in the first half of this year. We do plan to open-label Phase II study in the middle of this year to generate some open-label data provided further conviction around the profile of JADE101 to be able to report at medical conferences, but we don't think that Phase II data is gating necessarily for the Phase III. We've seen other sponsors go very efficiently into registration programs, and we think with the detailed characterization of the biomarker responses from the first-in-human study, we can have discussions with the FDA around what a registration program looks like in this evolving landscape of IgAN with multiple approvals now, and plan to move as quickly as possible into that registration program. Obviously, we're not first-in-class. So it's important for us to execute rapidly on this program to move it forward quickly.

This is a question about the market opportunity. What did Jade learn from ASN data and the Otsuka label? And maybe also comment on pricing.

Yes. I think I alluded to it in the presentation, but this is potentially going to be a much larger opportunity than a lot of people had appreciated. The epidemiological cost-led surveys that we look at show there's about 170,000 patients in the U.S. alone. Some other sources, I think Otsuka is quoting 205,000. So it's a sizable opportunity. And if you think that 60% to 75% of those are treated and eligible above 0.5 gram a day, that's a sizable population.

There are 2 key things that came out of Otsuka's approval of sibeprenlimab in November. One was the pricing, like you mentioned. They priced at really the higher end of the range of anybody's anticipation. So we've seen published reports that they're pricing at $30,000 per vial. So it's $360,000 to $390,000 per year. I think most analyst models had about $200,000 to $250,000, so really upsizing the commercial potential there. So that's one piece of the market sizing. It's always price times volume.

The other element that's driving this to be larger than we had anticipated is that every IgAN product that was historically approved, always had a proteinuria cutoff to reserve the drugs for more severe patients that are at more risk of rapid disease progression. So the earlier drugs with accelerated approval had a cutoff. You had to be generally over 1.5 grams per day that would come down to 1 gram a day kind of similar to their inclusion criteria in their Phase III upon full approval, but what we saw with the sibeprenlimab label was that they actually got quite a broad label with no proteinuria cutoff restriction.

So we think really that opens up the eligible treatment population to really that full 60% to 75% of patients that are at risk of progression above 0.5 gram a day. So our initial kind of calculations of a $10 billion market opportunity, you take that math, and that actually doesn't make much sense anymore. We actually looked at a report yesterday from Goldman Sachs that sets quoting it's probably more like a $40 billion opportunity.

So those are big numbers, but it is a significant opportunity where there's going to be multiple winners here, lots of room for multiple agents, but we think with our profile of that highest clinical activity possible to the mechanism plus the longest dose interval, the most convenient, we'll be able to take a sizable part of that market.

This is the final question for JADE101, and then we'll move to the rest of the pipeline. And this is a question about competitive dynamics. So clearly, it's a large market, but there are a lot of players. What are the main ways that you think you can differentiate with JADE101?

Do you want to take that?

Yes. As Tom mentioned during the presentation, we do think anti-APRILs are going to become frontline therapy for IgAN, and we want to deliver a best-in-class profile for the anti-APRIL mechanism of action. That's the combination of the full clinical benefit available to this MOA. We don't think any of the agents further advanced in development or approved are fully capturing the full magnitude of efficacy available. And we believe with JADE101's ultra-high binding affinity and half-life extension, we can more completely suppress APRIL throughout an extended dosing interval to deliver the best efficacy available.

We've seen in sibeprenlimab's Phase II study, a nice dose response such that the best clinical activity, the greatest reductions in proteinuria, the highest rates of clinical remission were achieved with full APRIL suppression. So we hope to deliver that with our Phase III profile and do it with a convenient and frequent subcu dosing schedule. So no more than 6 injections per year for these young, otherwise healthy IgAN patients.

These are questions now about JADE201. We didn't really have much time to -- we quickly went through it. Can you walk us through the mechanism of action? And how is it differentiated from other B-cell depleting agents?

Yes. So it really does address some of the limitations of the first-generation B-cell depleting strategies. B-cell depleters are generally pretty effective at peripheral circulating B-cell depletion, but are not as effective as tissue B-cell depletion, and tissue B cells are probably the key source of auto reactivity and autoimmunity, and they're also what drives tissue injury through pro-inflammatory responses. The other implementation of conventional B-cell strategies is that in response to B-cell depletion, you get these large increases in BAFF that add to repopulate the B cells, but also thought to exacerbate auto reactivity and autoimmunity, and can lead to relapses and flares on current B-cell depleting strategies.

So this dual mechanism of action for a half-life extended afucosylated anti-BAFF-R receptor monoclonal antibody addresses some of those limitations. Firstly, it uses enhanced effector function through ADCC to kill B cells through NK cells to get this deep peripheral circulating B cell depletion of BAFF-R receptor positive B cells. So that's immature through plasma loss of B cells, B cells involved in antigen presentation, autoantibody production as well as pro-inflammatory responses.

However, in the absence of sufficient effector cells like NK cells, this becomes particularly important in tissues where NK cells are sparse and other B cell depleters are not very effective at depleting those tissue B cells, JADE201 binds the BAFF receptor and blocks pharmacological stimulation from that elevated BAFF. So it prevents this important proactivation, pro-survival, pro-inflammatory signal to B cells, ultimately resulting in tissue B cell depletion through starvation of this important B cell survival factor.

Novartis has reported with ianalumab really impressive tissue B-cell depletion in the clinical setting, 84% decrease in salivary gland B cells from Sjogren's disease patients with 24 weeks of treatment of ionalumab, clinically validating this important differentiated dual mechanism of action.

We have a few minutes left, so we'll try to get through the rest here. Can you talk through the time lines of your Phase I in rheumatoid arthritis? What success looks like? And what other indications you might go into?

Do you want to talk to the Phase I, and I'll talk about other indications?

So on track to initiate a first-in-human in the second quarter of this year. That will be in rheumatoid arthritis patients, but really can be viewed as a surrogate for healthy volunteers for a B-cell depleter, an opportunity for us to generate safety tolerability data, but also very biomarker-rich PK/PD data, including the extended half-life of JADE201, BAFF receptor occupancy, which we believe we will measure directly and is a driver of clinical efficacy with this mechanism of action as well as detailed B-cell depletion and recovery through flow cytometry.

We'll opportunistically capture exploratory efficacy measures of joint pain and swelling in a DAS28 score, although not really anchored around that given the study design and limited sample size for this first-in-human study. So success would look like a safety, PK and PD profile that supports future development in a variety of different autoimmune diseases with an extended subcu dosing interval.

Yes. And as I mentioned in the presentation, in terms of indications, this is a really broad potential opportunity. Our estimates are there's 17 million patients in the U.S. with the indications where we could potentially go into representing a total $80 billion opportunity. So lots of opportunity, but we have to choose carefully as a smaller company where we allocate our capital. We do have a bit of a luxury of time while we wait for data from this RA study to really characterize the drug to be able to figure out where the best places are to differentiate, but during that time, we will see more information from ianalumab. As I mentioned, they're in 6 different Phase IIIs.

They're in Sjogren's, in ITT, in SLE, lupus nephritis, warm AIHA and systemic sclerosis, and we'll be able to see more data there and really understand where is the best place to differentiate, what kind of a trial can we run to really understand that in those indications, but then also, we have a lot of other promising indications where rituximab is the standard of care. We can go directly head-to-head versus rituximab or think about potentially relapsed/refractory patients for a good opportunity. And we're evaluating those indications as well where Novartis hasn't gone, as we mentioned, for potentially strategic or pipeline prioritization reasons. And there's several very interesting indications there that we could go after as well for a first-in-class strategy too.

We have time for one more question. Can you give us any insights into the JADE003 program?

No. So we aren't disclosing that. We have nominated the development candidate. It is -- for competitive reasons, we have seen like when we disclose targets that you do get a lot of other agents pop up and chase. So we want to get closer to the clinic before we disclose that. We will disclose it at some point this year, but I can reiterate, it is following that same playbook. There is an asset that's further ahead that has shown good clinical validation of the target, but we do believe with our protein engineering half-life extension technology, we can get a much better profile.

So better coverage of the target through the dosing interval, better length of dosing for patients to make it much more convenient to reduce treatment burden. What we are saying is, it is a bit more of a discrete target in terms of the indication potential. So it's not like 201 that can be applied to multiple different autoimmune diseases. It's more 101 like where there's kind of a lead obvious indication to go into.

Thank you. That is all the time we have for today's session. Thank you all for coming to the talk and to the conference.