Jade Biosciences, Inc. (JBIO) Earnings Call Transcript & Summary

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 Jay'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, janbiosciences.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 II development for the treatment of IgA nephropathy or IgAN, a chronic autoimmune disease that the 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 bale maintenance dosing from a single subcutaneous injection. Following our positive interim Phase I 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 II data for JADE101 in 2027 and anticipate initiation of our Phase III registrational trial of JADE101 in the first half of 2027 pending FDA alignment. Next in our pipeline is JADE201 a half-life extended AP cost-weighted 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 301, our potentially best-in-class half-life extended anti-interferon beta monoclonal antibody in development for dermatomyositis. On to Slide 4. I -- 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 EDPV. 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 clinically validated therapeutic 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 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 III development for DM. We believe these results support JADE301's potential is a best-in-class anti-interferon therapy. We expect to initiate a Phase I 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 Agarwal, pastor 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. Agarwal 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, he'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. Agarwal, allow me to first review the current and emerging treatment landscape on Slide 5, which underscores our conviction in JADE301's potential best in is profile based on its mechanism and intended subcutaneous administration. To orient you to the data on the table, efficacy in DM is measured primarily through 2 end points 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 for 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 and TM is quite burdensome for patients rely 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 anal risks. Repositinib, which was recently approved, presents an important advance. However, as a T2 inhibitor, its 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 [indiscernible] and hitting the interferon pathway more broadly including both inter front alpha and beta and potentially increasing the risk of viral infection and reactivation. Efgartigimod, which is also dosed weekly subcu and in the 5 mill formulation works through the cRn antinism, and therefore, may not address the underlying interferon-based ology implicated both in skin and muscle disease. Lastly, as you can see here, dazukibart, a selective intefromd 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 utaneous and muscle components of the disease, a clean safety profile and convenient administration to minimize treatment burden by parent selective interferon beta neutralization with subcutaneous dosing, our aim for JADE301 is best in disease clinical activity with a well-tolerated profile and the convenient dosing regimen. With that, I'll now turn the call over to Dr. Agarwal 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 a serious deblitating 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 experienced chronic painful disease with profound impact on their activities of daily living, underscoring the need for more effective treatment as well as better tolerated in 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 it 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 scheme 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 decision still require balancing efficacy, safety, steroid burden as well as convenience. No single therapy is ideal for every patient and treatment offer needs to individualize 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 a 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 related 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 ideally, we would like to target the pathway, which is most responsible for this activity while preserving as much as possible the normal immune function of other pathways. We also know interferon beta sets 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 III trial for dermatomyositis. From a clinical perspective, a Phase II 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 study, patients treated with dazukibart demonstrated substantial improvement in cutaneous disease activity as measured by CDASI.In fact, 82% of the patient treated achieved at least 40% reduction in and the magnude of improvement was notably greater than placebo across the dose clubs. You can see the resolution of skin disease in the images on this slide. Importantly, the benefit were not limited to skin. The study also showed improvement in test or total improvement score, including patients with more prominent muscle involvement. And the therapy was generally well tolerated. As a clinician, we are always doing efficacy against the realities of long-term treatment. While these data validate the interferon beta as a therapeutic target, the treatment burden means an important consideration 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. Agalwal, 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 of 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 anybody 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 halo 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 more 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 with a dosing profile that may meaningfully reduce treatment burden 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 in parallel 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 pM versus 28 pM. 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 STA 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 fiberglass 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 in muscle of DM patients. The IC50 of JADE301 was 11 pM compared to 91 pM for dazukibart, representing an approximately 8-fold improvement in functional potency. These data demonstrate that JADE301 minds selective high-affinity interferon beta binding with protein downstream interferon pathway inhibition across mobile experimental systems, supporting the potential of JADE301 to block the aberrant interferon beta signaling characteristic of [indiscernible]. 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 admiration of a single 30-milligram per kilogram dose of JADE301 in NHPs, the PK profile was characterized by a 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 the half-life extension has been successfully incorporated into the JADE301 molecule, supporting its ability to potentially provide prolonged systemic exposure and 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 for JADE301 in nonhuman primates along with the predicted favorable subcutaneous bioavailability supports the potential for our differentiated dosing profile and reduce patient burden compared to dazukibart, which requires high IV noises 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 I 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 I initiation expected in the fourth quarter of this year and interim data anticipated in the second half of 2027. With cash runway extended 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 lines for questions.

[Operator Instructions] Our question will be coming from the line of Alex Thomson 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 2H 27 interim? I guess what do you need to see you 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 IIb? Or is the POC certain in year?

Yes. Thanks, Patrick. We really appreciate the question. Ed, do you want to talk a little bit about the development pathway after Phase I?

Sure. Yes. So I think the Phase I, 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 III readout. So I think that will help inform things as well.

Yes. Maybe just to add to that. Yes, out of the Phase I, 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 is 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 the 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 at the data emerges.

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

Dr. Agarwal, 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 I beta 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. Agarwal, why don't you talk a little bit [indiscernible] and then hand it over to Andrew to talk about the expectations around the Phase I data.

Sure. So basically, each patient is very different. So there are different constellation of symptoms that everybody would report. But mostly, patients would report difficulty in activity of daily living. The things that you may 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 that -- we don't even think is difficult for our patient. That's 1 thing they complain. The second thing they complain if their rash is not the cosmetic part of the rash, it's painful quality of life altering part of the rash is painful burning the that really drives them crazy, not so much the cosmetic part. And the third most debilitating symptoms that I hear is the lungs where they have shortness of breath or cough, and when they -- as you know, many of my myositis patient 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 muscles, some may have mix of all. So every patient is a different story. So maybe ovef to Andrew.

Yes. Thanks for the question, Tyler. The Phase I study will primarily be focused on pharmacokinetics for guidance on the dosing strategy moving forward. Unfortunately, interferon beta is negligible in its expression in health volunteers. So there's no direct way to get [indiscernible] 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 pending 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 sets 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 your question is antibodies distribute at relatively low levels to the muscle, the important type organ of injury leading to the muscle weakness Dr. Agarwal 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 Trough 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 IC 99s 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 [indiscernible]. Do you decide to do steroid tapering in Phase II or not? And I think 1 of the unique things about the Pfizer development plan is they kind of split out the 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 III?

Thanks, Akash. Yes, a really good question. Yes, we've been looking at that Pfizer designed 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 DMP 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. And 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 II is exactly what you pointed out. they had a much more significant population of skin only with a higher CDASI requirements, 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 manifestations. So our our view in terms of the inclusion criteria would be to ensure that the 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 a follow-up on that. In terms of incorporating steroid tapering in Phase II, would that it sounds like, yes, you will have steroid tapering in Phase II.

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

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

Just a couple of housekeeping questions. First, apologies if I missed it, but on the Phase I study design, have you disclosed the dose amounts 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 I? And then one for Dr. Agarwal, just out of curiosity with a couple of different mechanisms advancing -- how do you envision physicians making selection choices on which therapies used 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. Agarwal, if you could talk about how you select which class of agents for which patients.

Yes. That's 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 Myers. So that provides the greatest potential mitigation of immunogenicity, but being fully human by design. We will be measuring ADA rates and the impact on in the healthy volunteer study, but by design have attempted to reduce the risk of immunogenicity for the program.

Thanks, Andrer. And Dr. Agarwal, can you just comment on selection?

Yes, I can speak to it. So basically, the concept that what your question is rather rather than which one I would prefer 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 dermatomyositis. Because it's a chronic disease, and we have -- just to give you an example, dermatomyositis is a 21 drugs approved. It is only the fight is which 1 I would use first. But if I look at the history of my patients over 10 years, 20 years, chronic inflammatory autoimmune conditions, almost in most of my patients that we use a bunch of them, 6, 7, 8 agents have been used over the life. Because what happens is that 1 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 1 I would use first. And which of these mechanisms 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 Jack Tech pathway, IVIG and interferon pathway. [indiscernible] and interferon part, we are pretty much the same pathway. So simpler drugs such as oral would would be preferred the 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 a severe cardiovascular risk, then maybe would drug would be preferred over other. Patients may have pregnancy than 1 drug IVIG may be preferred over others. So there many nuances when you talk about individual patients, which are which drug I would prefer first. But what I do believe in each disease states of myositis such as dermatomyositis, we need multiple mechanism of action in 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 Tazo's PK/PD profile from the standpoint of saturating or covering the target such that our drug, which is more potent and may require less drug, we'll have room or opportunity to be higher efficacy than what Pfizer is doing in an IV formulation, probably giving a lot of drug. That's question one. Question 2 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 product development plan, would that be something that could be interesting in Phase II 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 1 as well, which is the -- what we learned from dazukibart that we can apply. And then I'm happy to talk about the indications.

Yes. We have looked at all the publicly available PK/PD modeling, including from the patents from dazukibart. Unfortunately, it's not a particular biomarker rich disease state, as I mentioned previously, there's low levels of circulating interferon beta, it's difficult to get direct assessments of target engagement based on translational modeling that 600-milligram dose does appear to be covering the IC 99 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 import 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 [indiscernible] broader than just DM given the landscape.

And I just recall, you did ask about learning from the dazukibart experience when we expect to see more information. We actually just saw a recent publication from [indiscernible] safety signal. So consistent with the initial clinical experience of a safe and well-tolerated mechanism. The next major learning will come from the Phase III trial that's currently ongoing. It's on clinicaltrials.gov completion date in the middle of 2027 8. So that will provide significant [indiscernible] of the interferon beta and also provide some potential in [indiscernible], which also is being enrolled in that trial. And that could be is important guide for potential life cycle management indication expansion. But I'll turn it back to Tom to continue on the broader potential of JADE301 in outside of DM.