Eliem Therapeutics Inc Aktie

Good morning, and welcome to the Climb Bio Investors' event focused on Budoprutug and the CD19 opportunity. [Operator Instructions] Please note, this call is being recorded. I would now like to turn the conference over to Dr. Carlo Tanzi of Kendall Investor Relations. Please go ahead.

Thank you, and good morning. Prior to today's webcast, the company posted a presentation to its website, which can be found under the Investors and News section. Please note that various remarks that may be made during today's presentation about future expectations, plans and prospects for Climb Bio, expectations regarding the therapeutic benefits, clinical potential and clinical development of budoprutug and CLYM116, the anticipated time lines for reporting initial data from Climb Bio's ongoing and planned clinical trials of budoprutug and CLYM116, the anticipated time line for initiating Climb Bio's parallel Phase Ib clinical trial of budoprutug in patients with SLE in China, the potential commercial opportunity and limited competitive landscape for budoprutug, the expected patient populations in pMN, ITP and SLE, the expected benefits of budoprutug's Fast Track Designation and Orphan Drug Designation in pMN, the sufficiency of Climb Bio's cash resources for the period anticipated and other statements which are not historical facts.

Actual results may differ materially from those contained in these forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of our most recent annual report on Form 10-K, which is on file with the SEC. In addition, any forward-looking statements made on today's call represent Climb Bio's views as of today only and should not be relied upon as representing its views as of any subsequent date. While we may elect to update these statements at some point in the future, we specifically disclaim any obligation to do so unless required by law. Any forward-looking statements should not be relied upon as representing Climb Bio's estimates or views as of any date subsequent to today.

Today, I am joined by Climb Bio's President and CEO, Dr. Aoife Brennan; Dr. Edgar Charles, Climb Bio's Chief Medical Officer. In addition, we are pleased to include Dr. David Jayne, a practicing physician and Professor of Clinical Autoimmunity at the University of Cambridge and Director of the Vasculitis and Lupus Service at Addenbrooke's Hospital. Following the presentation, we will open the call to a Q&A session, which will also include additional members of the Climb Bio management team, Dr. Perrin Wilson, Chief Business Officer; and Dr. Susan Altschuller, Chief Financial Officer. And with that, I'll pass the call on to Aoife.

Thank you, Carlo, and thank you all for joining us for this R&D spotlight event focused on CD19 and our lead asset, budoprutug, and its potential in immune-mediated diseases. At Climb, our strategy is focused and deliberate. We're delivering differentiated monoclonal antibodies against validated B-cell targets with clear development paths in indications, including those impacting kidney health that offer potentially meaningful therapeutic and commercial opportunity. We set a high bar for success, and we're making strong progress across our portfolio.

Following a foundational year of execution in 2025, we're entering a data-rich period with anticipated readouts across all of our ongoing studies this year. Before turning to budoprutug, I will briefly touch on our other asset, CLYM116, which is also progressing well. CLYM116 is a next-generation anti-APRIL monoclonal antibody with the potential to deliver a best-in-class clinical profile in IgAN and other B-cell-mediated diseases. It is the only sweeper monoclonal currently in development targeting APRIL.

We in-licensed this asset in January '25 and rapidly generated head-to-head preclinical data versus a first-generation anti-APRIL antibody, suggesting the potential for greater potency and longer dosing intervals with low immunogenicity. CLYM116 is currently being evaluated in 2 parallel Phase I studies, one conducted by the Climb team and one by our partner in China, MabWorks, which together will provide a comprehensive data set from healthy volunteers. We will present data at the upcoming European Renal Association meeting in June. This presentation will include modeling data from nonhuman primates that supported the design of both first-in-human studies as well as initial safety data from our ongoing Phase I study in healthy volunteers.

Further data from the Climb-led healthy volunteer study, including biomarker data will be presented at a dedicated CLYM116 spotlight event midyear. Today, we're shining our spotlight on Budo. Our CD19 monoclonal antibody currently in clinical studies across pMN, ITP and SLE, with recently completed healthy volunteer study of our subcutaneous formulation. Budo is designed to deliver B-cell depletion that is broad, deep and sustained through a scalable and well-understood monoclonal antibody approach. While CD19 is often described as a crowded space, the reality is quite different. There are very few monoclonal antibodies in development targeting CD19 for B-cell depletion in immune-mediated diseases.

In contrast, there are numerous complex modalities targeting CD19, which require administration in specialist referral centers given the need for specially trained staff and the ability to monitor patients for potential acute safety risks. As a result, Mab targeting of CD19 represents a clear and attractive white space. The opportunity for CD19 targeting monoclonal antibody is substantial. This has been validated by inebilizumab or UPLIZNA, which has demonstrated commercial success in rare neurological indications with increasing consensus projections since launch. We believe the advantages of the monoclonal antibody modality, including scalability, established safety and the potential to deliver durable long-term disease control support expanding this approach into additional indications.

This is the path we are pursuing with Budo. Our goal is to develop Budo for patients who remain underserved by available therapies, delivering not only robust clinical outcomes, but also a therapy that can be safely and conveniently administered in real-world care settings. With that in mind, we're delighted to be sharing data from our recently completed trial of the subcutaneous formulation of Budo on today's call, demonstrating encouraging activity and supporting further development. We are currently advancing Budo across 3 target indications: pMN, ITP and SLE. These are indications where B cells are central drivers of disease, spanning renal, hematologic and rheumatologic conditions with significant unmet need.

Importantly, Budo was recently granted Fast Track Designation by the FDA for the treatment of primary membranous nephropathy, underscoring both the urgency of need and its potential to deliver meaningful benefit. Budo's differentiated profile supports broad potential applicability across multiple indications, representing an expansive market opportunity. We expect to share initial data from our ongoing studies in pMN, ITP and SLE later this year, and Edgar will walk through each of these indications, the study design and upcoming milestones in more detail in a few moments.

But first, to help ground today's discussion, I am pleased to introduce Dr. David Jayne, a renowned physician and scientist at the University of Cambridge and Addenbrooke's Hospital with deep expertise in B-cell depletion and immune-mediated diseases. He will share his perspective on 2 key questions. How does CD19 compared to CD20 as a target for B-cell depletion? And can a monoclonal antibody deplete tissue-resident pathogenic B cells? Dr. Jayne, thank you for joining us. I'll hand it over to you.

Thank you for inviting me to say a few words about targeting CD19 for autoimmune disease. My name is Dr. David Jayne, and I'm from the University of Cambridge in the United Kingdom. B cells have several important functions in autoimmunity. They can develop into plasmablasts and plasma cells that generate pathogenic antibodies. And these are seen, for example, in primary membranous nephropathy, ITP and in lupus or SLE. B cells also support T cell autoreactivity, and this has been shown in a variety of autoimmune conditions, including rheumatoid arthritis and multiple sclerosis. B cells have typically been targeted therapeutically by anti-CD20 monoclonal antibodies, such as rituximab or ocrelizumab. However, over the last 2 decades, various limitations have been identified with targeting CD20.

Firstly, CD20 directed treatment fails to completely remove circulating autoantibodies. The graph on the left shows changes in anti-double-stranded DNA antibodies in SLE with rituximab. And what you can see is although there are reductions in anti-double-stranded DNA antibody levels with rituximab in the majority of patients levels remain well above baseline. So they continue to have positive antibodies despite rituximab. Another aspect is that there is incomplete removal of tissue resident B cells with CD20 targeting. And we know tissue-resident B cells play important roles in pathogenesis. Tissue resident B cells are important in several different scenarios. In the example at the bottom on the right are B-cell infiltrates in the kidneys of patients with lupus nephritis. And these infiltrates are important negative prognostic features in the long-term outcome of lupus nephritis patients that are not adequately targeted by CD20. So the consequence of these limitations is that CD20 targeting only has partial efficacy and when it wears off, there is a high relapse rate.

So why target CD19? CD19 promotes the growth, activation, proliferation and signaling of B lymphocytes. CD19 positive cells play an important role in the pathogenesis of autoimmune disorders. CD19 has a broader distribution than CD20 within the B-cell and plasma-cell compartments. Also, we have experimental examples from preclinical models and in humans that hyperrexpression of CD19 is associated with autoimmunity. So further building on the rationale for use of CD19 strategies, this cartoon describes the development of B cells from pro B cells in the bone marrow all the way through the periphery to mature B cells and then plasma cells back in the bone marrow. And as you can see, the different cell surface markers are expressed at different stages of development, with CD19 appearing early on pro B-cells and continuing to be expressed unlike CD20 on plasmablasts and many plasma cells.

CD19 targets other pathogenic B-cell subsets. An example of this is the so-called double negative B cells, which are precursors of autoantibody secreting B cells and have shown to be expanded in autoimmune diseases such as SLE. And they're defined by a particular set of surface antigens. Other key roles of CD19 in pathogenesis are autoantibody secreting plasma cells. Plasma cells in rituximab refractory autoimmune patients can be targeted by CD19 and as they do not express CD20. In fact, clinical remission of rituximab refractory autoimmune disease can be induced by anti-CD19 chimeric antigen receptor T cells or CAR T cells. CD19 positive plasma cells are not short-lived plasmablasts, and they may have a much longer lifespan than plasmablasts. Autoantigen binding B cells and CD19 positive plasma cells serve a critical role in perpetuating T cell activation in autoimmune disease.

Moving to some practical examples. This is a patient who's received CD19-targeted CAR T therapy for vasculitis. The upper panels show the UMAP transcription profile before CAR T from a bone marrow biopsy and the lower panels show cells from a post CAR T bone marrow biopsy. The highlighted area is the B-cell compartment. And you can see that the B-cell compartment has been completely depleted by CD19 directed CAR T therapy. Looking at this concept in more detail, in this study, anti-CD19 CAR T therapy was compared to anti-CD19 T-cell engager therapy and anti-CD20 depletion with rituximab or obinutuzumab with respect to the ability to deplete tissue resident B cells.

Consistent with what I showed you on the previous slide, you can see in the right-hand panel that after CD19 targeted CAR T therapy, there's complete removal of B cells from the lymph node. It was also observed that the follicular structures comprised of dendritic cells, T cells together with B cells and which support germinal center formation and thus autoantibody formation were disrupted by CD19 directed CAR T therapy. In the central column, you can see in the bottom panel that B cells are abundantly present in the lymph node after rituximab treatment. Rituximab is not depleting the B cells in the lymph node very well at all. However, with obinutuzumab in the left-hand panel, there is substantial B-cell depletion, even better than what was observed with the T cell engager. Moreover, a reduction in follicular structures was also observed.

Taken together, these results suggest that a large degree of tissue level B-cell depletion can, in fact, occur with a conventional monoclonal antibody approach. It is reasonable to hypothesize that even deeper B-cell depletion can be achieved by a monoclonal antibody that targets CD19.

So to conclude, durable remissions are associated with deep B-cell depletion and with depletion of plasma cells and can potentially be achieved with conventional monoclonal antibodies. Targeting CD19 rather than CD20 offers the potential for more complete B-cell and plasma cell depletion. This is likely to be particularly important in removing pathogenic antibodies relevant for the treatment of many autoimmune diseases. Thank you.

Thank you, Dr. Jayne, for those insights, particularly your perspective on the depth of B-cell depletion and the potential value of CD19 as a therapeutic target. What you've highlighted reinforces the scientific rationale for targeting CD19 instead of CD20 and the potential of a CD19 monoclonal antibody approach in treating autoimmune disease. With that foundation in place, I'll now walk through how we're translating this biology into clinical development across our key indications, including pMN, ITP and SLE and what we expect to learn from our ongoing studies.

CD19 is emerging as a preferred pan-B-cell target for B-cell depletion. CD19 is expressed from early B-cell development, the pro B-cell stage through mature B cells and antibody secreting plasmablasts and on a substantial proportion of plasma cells. CD19 has broader B-cell expression coverage than CD20, which is not present on pro B-cells, plasmablasts or plasma cells. This broader expression profile allows for more comprehensive depletion of the B-cell lineage, including the cells most responsible for pathogenic antibody generation.

Importantly, since CD19 is not expressed on long-lived plasma cells, targeting CD19 is not expected to impair the protective antibodies, such as those induced by vaccines, which are important for preventing infection. Budoprutug is an investigational CD19 targeting monoclonal antibody with low picomolar affinity for CD19. And it has been specifically engineered with low fucosylation to enhance engagement of immune effector mechanisms, including antibody-dependent cellular cytotoxicity.

In preclinical studies, budoprutug demonstrated high potency and achieved robust and consistent B-cell depletion across physiologic compartments. Importantly, this is realized within a conventional monoclonal antibody framework, combining potency with the predictability, scalability and clinical familiarity of a well-established modality. The combination of CD19 biology and Fc-enhanced design provides budoprutug with the potential to achieve deep B-cell depletion, including effects on tissue resident and antibody-producing cells that may not be fully addressed by therapies that target CD20. We have evidence from a human CD19 transgenic mouse model showing budoprutug's ability to achieve depletion of tissue resident B cells in peripheral lymph nodes and bone marrow.

While this transgenic model likely underestimates the potential of budoprutug tissue B-cell depletion as the mouse does not have all the components of the human immune system. It does demonstrate the ability of budoprutug to act not only in the periphery but at the tissue level. We have further studies underway to support the potential for tissue level depletion with budoprutug. We believe the depth and breadth of B-cell depletion is important, not just for controlling disease activity, but potentially for restoring normal B-cell homeostasis. Ultimately, this provides a rationale for exploring disease-modifying approaches with the goal of achieving durable clinical benefit and potentially treatment-free remission.

As we have previously presented, in the pilot study in patients with pMN, budoprutug dosed at either 100 milligrams or 200 milligram has demonstrated compelling proof of concept with the potential for long-term disease remission. In this study, budoprutug achieved complete peripheral B-cell depletion in 5 of 5 evaluable patients. This effect was observed at a low dose of budoprutug with reduction sustained out to 1 year after just 2 dose cycles. This robust B-cell depletion was followed by compelling reductions in pathogenic autoantibody levels as well as reductions in proteinuria, leading to clinical remission in all 5 patients and complete remission in 3 out of 5 patients.

Remission was maintained for up to 3 years in the 4 patients who received 4 doses of budoprutug and who were followed long term, with 3 out of the 4 patients not requiring any further immunosuppression. While this was a small data set, the durability of the clinical response after just 4 doses of budoprutug is particularly encouraging and provides early validation that budoprutug's mechanism is translating clinically.

Based on this compelling initial proof-of-concept data, we are advancing budoprutug across multiple immune-mediated diseases where B cells are central drivers of pathology and where an anti-CD19 monoclonal approach has the potential to address an unmet need. This parallel development approach allows us to generate insights across indications, informing the ability to achieve B-cell depletion, defining the optimal dose in renal and nonrenal indications and assessing the potential for long-term disease control.

From here, I'm going to highlight each indication in more detail, covering the unmet need, scientific and translational rationale and clinical trial designs. I'll also share top line data from our Phase I study of the budoprutug subcutaneous formulation in healthy volunteers and our next steps for development. We'll start with pMN. PMN is a progressive antibody-driven renal disease that can lead to significant morbidity, including nephrotic syndrome, chronic kidney disease and ultimately, kidney failure. The goal of treatment is to reduce proteinuria and induce clinical remission, which has been associated with decreased progression of kidney disease and development of kidney failure. Despite substantial advances in understanding disease biology, outcomes remain suboptimal for many patients.

Targeting CD19 positive B cells has the potential to address the core disease drivers in pMN in which pathogenic IgG4 autoantibodies are produced by CD19-positive B cells. These pathogenic autoantibodies bind the PLA2R antigen on the podocytes, leading to local formation and growth of immune complexes on the outer surface of the glomerular basement membrane. Recruitment of complement to the immune complex leads to podocyte cell injury, loss of slit diaphragms between the podocytes and consequent leakage of increasing amounts of protein into the urine. This direct cause and effect relationship between autoantibody producing CD19-positive B cells and pathogenic destruction of the glomerular filtration barrier provides a clear biological rationale for targeting CD19 positive B cells in pMN.

PLA2R autoantibodies are the primary pathogenic driver in approximately 75% of pMN patients and are reflective of ongoing immunologic disease. Importantly, disappearance of PLA2R antibodies precedes reduction in proteinuria and clinical remission, which are reflective of restoration of the kidney filtration barrier. PLA2R antibody levels provide prognostic insight into the disease course as higher titers are associated with a greater risk of kidney disease progression. Since the presence of PLA2R antibodies is indicative of ongoing immunologic dysregulation, PLA2R antibodies serve as a clinically important early biomarker of therapeutic responses for agents such as budoprutug to target B cells, the root cause of pMN. Despite advances in understanding disease biology, there are no currently approved therapies for pMN. Treatment approaches remain variable, often relying on broad immunosuppression despite its associated safety risks and comorbidities.

KDIGO guidelines recommend treatment with rituximab, cyclophosphamide or calcineurin therapy based upon risk estimate, which incorporates PLA2R antibody levels. Rituximab, although not approved for pMN, has been shown in the MENTOR study to be superior to cyclosporine in maintaining proteinuria remission up to 2 years, providing proof of concept for B-cell depletion as a therapeutic option in pMN. However, complete remission rates in the MENTOR study were low. And at 2 years, only 35% of patients achieved complete remission, which is the treatment goal to prevent kidney decline.

Given the lack of approved treatments, there remains clear unmet need for a therapy that more directly and completely addresses the pathogenic biology of pMN and delivers improved outcomes for patients. PMN represents a well-defined patient population with significant unmet need for therapies that are both more effective and well tolerated. Approximately 75,000 patients in the U.S. have pMN, and it is a leading cause of nephrotic syndrome in adults. While about 1/3 of patients may achieve spontaneous remission, the majority, particularly those with moderate to high-risk disease, do not achieve spontaneous remission, and they are at risk for progressive kidney disease. It is these patients who are predisposed to complications and progressive kidney failure and for whom KDIGO recommends use of immunotherapy.

Data from the completed Phase Ib study in pMN suggests a compelling competitive profile for budoprutug. Although there are several investigational agents in development for pMN, none are currently approved, although rituximab is frequently used off-label. By targeting CD19, budoprutug has the potential to achieve pathogenically relevant B-cell depletion and immunologic and clinical remission with the potential for a highly competitive clinical profile. We are currently conducting the PrisMN trial, a global open-label dose escalation Phase II study in 45 patients with moderate to severe pMN. Dosing in this study begins at 200 milligrams, picking up for our Phase Ib trial left off, and it is evaluating doses up to 1,000 milligrams with the goal of maximizing B-cell depletion. The study is currently enrolling and it has a global footprint of approximately 45 sites across 8 countries.

The PrisMN study's biomarker endpoints, particularly B-cell depletion and PLA2R antibody levels are designed to make robust predictions of ultimate clinical efficacy and enable rapid identification of an optimal Phase III dose, providing for an accelerated development time line. Preliminary efficacy will also be evaluated through assessment of proteinuria and complete and partial remission rates. Safety and tolerability will also be evaluated through assessment of adverse events. The PrisMN study is progressing well, and we look forward to sharing additional data to further define budoprutug's potential in this indication. We anticipate initial B-cell depletion data and PLA2R antibody data from the low-dose 200-milligram cohort at 12 to 24 weeks in the fourth quarter of 2026. While the proteinuria data will take time to mature, we expect this early look at biomarkers to corroborate the B-cell and immunologic response data from our Phase Ib study.

Immune thrombocytopenia is a rare autoantibody-mediated disease characterized by platelet destruction and impaired platelet production. The resultant low platelet count not only confers a substantial bleeding risk, but it also impairs quality of life. Patients often experience easy bruising, fatigue, functional limitations, anxiety and depression.

Without disease-modifying treatments, the clinical burden of disease is high. This burden includes recurrent bleeding events, which can require hospitalization and frequent steroid dependency with this accompanying side effects. B cells are central to disease pathogenesis and ITP. B cells secrete autoantibodies directed against glycoproteins on the surface of platelets. The oxidized platelets are phagocytes by monocytes and splenic macrophages. Autoantibodies also bind to megakaryocytes that express surface glycoproteins like those on platelets. The deficient production of platelets in ITP is due to the abnormal humoral and cytotoxic responses directed against megakaryocytes in the bone marrow.

Targeting CD19 has the potential to address a root cause of ITP by eliminating the pathogenic autoantibody-producing B cells, offering a potentially disease-modifying approach for ITP. Rituximab, a standard off-label treatment for ITP has demonstrated the potential for B-cell depletion to alter the course of disease. However, rituximab has notable limitations, including incomplete B-cell depletion, underscoring the need for continued therapeutic innovation.

Notably, given the broader expression of CD19 across the B-cell lineage, targeting CD19 may overcome key limitations and approaches to targeting CD20 as CD19 is expressed on plasmablasts and many plasma cells, which drive autoantibody production, while CD20 is not. Published studies and clinical observations suggest that roughly 80% of ITP patients have limited durability of response following treatment with rituximab. Expansions of CD19-positive, CD20-negative plasma cells have been observed in the spleens of patients following rituximab treatment, indicating the emergence of rituximab-resistant autoantibody secreting cells following rituximab treatment.

Targeting CD19 positive populations, including plasmablasts and plasma cells, may enable more sustained reduction or elimination of pathogenic autoantibodies produced by these cells. First-line treatments for ITP include corticosteroids as well as IVIG and anti-D immunoglobulin. Many patients fail first-line therapy and cycle through subsequent treatments, including thrombopoietin receptor agonists, which are efficacious, but often require chronic administration and are also associated with side effects such as bone marrow reticulate formation and thrombotic complications. Rituximab is often used as off-label therapy, but as discussed on the previous slide, has notable limitations.

After second-line failure, SYK inhibitors and BTK inhibitors are typically used, but less than half of patients achieve overall response and less than 20% to 25% of patients achieve a durable response, leaving room for disease-modifying treatment options with a more compelling profile. We believe a substantial unmet need remains in ITP for a safe, efficacious therapy with a dosing regimen that provides an opportunity for treatment-free disease control. Chronic ITP patients often cycle through multiple therapies in order to maintain their platelet counts. A substantial proportion of patients progress to more advanced disease where treatment options are limited and durable responses are uncommon.

Notably, investigational therapies in ITP have not yet been able to improve upon this low level of response, suggesting a high unmet need remains for a more efficacious therapy. Safety and convenient dosing are also critical considerations in ITP given the decrease in quality of life that many patients are already experiencing as a result of the disease. Available therapies come with particular safety considerations and burdensome oral dosing and other emerging therapies may present a trade-off of frequent infusions. Previously treated patients with chronic ITP represent a high unmet need population and a high-value opportunity for improved therapies that address the underlying drivers of disease. We have included this underserved patient population in our ongoing ITP trial.

We are conducting a multicenter open-label dose-escalation study in previously treated ITP patients, including heavily pretreated individuals. The study is assessing 3 doses of budoprutug ranging from 250 milligrams to 1,000 milligrams. This trial is important not only for our exploration of ITP, but also for its ability to evaluate the safety, preliminary efficacy and dosing of milligrams in a nonrenal indication.

Enrollment in the first 2 cohorts is complete, and enrollment in Cohort 3 is expected to begin in the second quarter. The ITP study is designed to define dosing in a non-renal patient population and characterize B-cell depletion as well as both the depth and durability of platelet response, key parameters for assessing potential for long-term disease control in the previously treated ITP population. We anticipate sharing initial B-cell depletion and platelet response data from the low-dose 250 milligram cohort with follow-up out to 24 weeks at a medical meeting in June of 2026, with additional data from higher dose cohorts by year-end. We expect the data to define budoprutug's potential path forward in ITP and establish a dose in a nonrenal patient population.

As a reminder, patients in this study have been previously treated with at least one agent for ITP and the majority have cycled through multiple agents. This is a refractory patient population with remaining need for more effective, durable therapies. SLE is a complex autoimmune disease driven by autoreactive B cells and B-cell generated autoantibodies, making CD19 a highly relevant therapeutic target. While anti-CD20 therapies have demonstrated the promise of B-cell targeting, clinical outcomes remain variable and response is incomplete, highlighting the opportunity for improvement. CD19 targeting CAR T therapies have further validated CD19 as a therapeutic target with compelling efficacy, but they are limited by safety considerations, scalability challenges and access challenges.

A CD19 monoclonal antibody approach has the potential to provide patients with disease control and a more accessible administration format. We have 2 ongoing studies designed to generate translational insights, including the relationship between dose, B-cell depletion and clinical biomarkers to inform future development in this indication. While our global study begins at subtherapeutic doses and investigate single doses of budoprutug. Our parallel study in China will provide complementary data with higher repeated doses of budoprutug, and it will provide an accelerated path to decisional readout. We have set a rigorous bar for success, and we will want to see compelling evidence of therapeutic activity in order to advance development.

Each of our clinical trials of budoprutug in pMN, ITP and SLE utilizes an IV formulation. In parallel, we are developing a low viscosity, high concentration 175 milligram per ml subcutaneous formulation, which may offer a differentiated convenience profile for patients. We have recently completed a Phase I placebo-controlled single ascending dose study to evaluate the safety, tolerability and PK/PD of subcutaneous budoprutug in healthy volunteers. Participants received subcutaneous budoprutug at doses of either 3 milligrams or 6 milligrams, IV budoprutug at a dose of 6 milligrams or placebo.

Since this was a study in healthy volunteers and whom it's not appropriate to completely deplete B cells, budoprutug doses were selected to produce measurable but submaximal B-cell depletion. Safety profiles were comparable between the budoprutug subcutaneous and IV groups. PK interpretation for subcu doses was limited as most of the concentrations were below the limit of quantification. However, robust PD effects were observed. All active groups demonstrated rapid B-cell depletion, reaching approximately 80% reduction from baseline. B-cell depletion was similar between subcutaneous and IV administration arms, suggesting adequate systemic exposure to achieve robust PD activity.

To summarize, subcutaneous budoprutug showed robust effects on B-cell depletion in healthy volunteers with similar tolerability to max dose IV budoprutug despite being studied at doses predicted to produce only modest impacts on B cells. The totality of the data to date in nonhuman primates and healthy volunteers supports continued development of the subcu formulation. In NHPs, budoprutug exhibited high bioavailability as well as a favorable safety and tolerability profile. In healthy volunteers, there was comparable PD, safety and tolerability between the subcu and IV administration routes. These data support the feasibility of subcu administration and provide the rationale for continued development in immune-mediated diseases.

Our next step will be to advance the subcu formulation at full B-cell depleting doses in patients with autoimmune diseases and to identify the appropriate regimen for further development. Our ongoing clinical development program is building the foundation for budoprutug's potential long-term value across multiple B-cell-mediated diseases. By evaluating a broad dose range across renal and nonrenal indications, we are generating the data needed to demonstrate deep and durable B-cell depletion, confirm safety and tolerability and inform optimal dose selection for future pivotal trials. Upcoming data readouts throughout 2026 are expected to provide important validation of biological activity, including effects on B cells, autoantibodies and disease-relevant biomarkers. Together, these data and their milestones position the potential of budoprutug to support differentiated durable disease control and a scalable development path across multiple indications.

With that, I'll turn it back to you, Ia.

Thanks, Edgar and Dr. Jayne. As you heard, there are multiple immune-mediated diseases where patients have inadequate disease control with existing therapies. We are excited to be evaluating the potential of Budo to address these needs by targeting the pathogenic B cells that are the drivers of the disease pathology. As we look ahead, the data readouts expected throughout this year will be important in defining Budo's clinical profile. We believe Budo is well positioned to become a foundational therapy across a range of immune-mediated diseases, and we look forward to sharing our progress with you as the year unfolds.

Thank you again for joining us today. We'll now move into the Q&A portion of the webcast.

[Operator Instructions] Our first question will come from the line of Yasmeen Rahimi from Piper Sandler.

Thank you for very thoughtful present and discussion. Maybe the first question is, and thank you for more granular timing of the 3 data readouts. Given that the ITP, B-cell and platelet data is expected here for the low dose in June, maybe help us understand whether there is any translation from the B-cell response in ITP to pMN or SLE, which are expected later in the quarter? And also maybe help us think about now with really the subcu data on hand that continues to show a similar product profile to IV, how do you think about sort of what work is needed to advance the subcu into Phase III? And then maybe I'll have a last follow-up.

Thanks, Yas. This is Aoife here. I'll take the first one around kind of the read-through and pull and then hand it over to Edgar to talk about how we think about the subcu and dovetailing it into some of our development programs. So yes, you're right. We have an upcoming presentation of the early data from the ITP study. And I think the real -- there's probably 2 questions in each indication. Number one is can we deplete B cells deeply and durably at a well-tolerated dose. And I think that's something that we're going to learn from some of the initial readouts.

Then the second part of that is how does that B-cell depletion translate to clinical endpoint may be different across indications. So I think the data we see is instructive [ around the 1st March ], but there'll be some disease-specific issues and questions that we'll need to address within each of the indications we pursue because I do think the relationship between B-cell depletion and the clinical endpoints may be different in the various indications. So we're building the story here. We're derisking step by step. And I think that will continue as we go through the year and you start to see some of the data readouts that we have coming up. And then for the second part, maybe on subcu, I'll hand it off to Edgar, who'd be leading the charge on the development side.

So we already see some good signs with subcutaneous in healthy volunteers. And what we're really looking for is seeing a good, robust B-cell depletion at doses that we can take into patients with autoimmune disease. We're going to be going next to look at higher doses in patients, looking at safety tolerability as well as B-cell reductions. And ideally, we get to a place where we could have similar levels of B-cell reductions with subcu compared to the IV formulation. I think that opened up a lot of options for going into the indications in which we're already spending IV potentially as well as going into different indications. You can envision a variety of spaces where subcutaneous administration would be preferred to IV.

So maybe we'll move on and then I do to the queue at the end, if that's okay with you, just so that we can get through some of the other people we have in line.

Our next question will come from the line of Chris Raymond from Raymond James.

Just 2 questions. On the subcu formulation, I know this is early and you're testing it at lower doses here. But any sort of sense of what a dosing frequency might be in subcu? And maybe a part B to that question is with the subcu formulation, again, this is preliminary data, but if it continues to go well, why not advance this drug into gMG, which obviously is a derisked indication? And then the second question, I guess, I have is on pMN. The initial data you guys have at 100 milligrams and 200 milligrams look pretty promising, but I think you're taking it all the way up to 1,000. Maybe just what additional efficacy are you looking to see if you go that much higher?

Yes. So for the frequency question, I think that remains to be determined. We have some really nice data in healthy volunteers that we've shared today. I think continuing to study the full B-cell depleting dose in patients with autoimmune diseases will help inform and illuminate steps forward. I think broadly, there are kind of 2 approaches. Number one is give the equivalent of the IV regimen with the subcu route of administration. The other path that I think is also viable is to give lower doses more frequently, subcu enables that. So I think we will make that decision based on data, and we're gathering data now to really build and inform that model in how we might pursue subcu going forward.

Your second question about myasthenia gravis, I think is interesting. It's one that we get quite a lot given how well validated commercially, that opportunity is, and it's a very, very crowded space, and we'll continue to watch and see if there is an opportunity for us to do something for patients with the subcu B-cell depleter. But as of today, we're very much on the sidelines on myasthenia gravis and watching, obviously, the UPLIZNA launch, I think, will be informative of our decision around going forward as well as some other kind of emerging products in that space. But if we see there's an opportunity to deliver value for shareholders and something for patients that really move the needle, we would absolutely reconsider that.

Regarding dose in pMN, you're absolutely right. We saw encouraging signs in our initial study in pMN with 100 milligrams and 200 milligrams. We are pushing dose in our next study to achieve an even deeper B-cell depletion and perhaps even a better immunologic suppression and overall remission rate.

Our next question will come from the line of Joe Catanzaro from Mizuho.

Maybe a quick one for me. I guess maybe sort of following up on Chris' last question. But the PK/PD relationship that you guys are thinking about looking across this wide range of doses and maybe what the CD20 experience tells you. So as you go to higher doses, should we expect deeper B-cell depletion, faster B-cell depletion and/or more durable B-cell depletion? And I guess somewhat relatedly, when you look at CD20 experience in renal versus nonrenal, what does that tell you about where you could land with Budo in renal and nonrenal indications?

Yes. I think to follow on to Edgar's answer around the pMN study, what's really important here is that we make sure that we get the right dose before we initiate Phase III. And you have only one opportunity to do that, and that's in your Phase II program. And we clearly pointed out that there may be a renal and a nonrenal dose. The reason being that these pMN patients often have a lot of proteinuria at baseline when you're dosing them, you're only giving 2 IV infusions at baseline. And if you're losing 30% to 40% of that protein in your urine because of the high baseline proteinuria in these patients, that's obviously going to impact exposure and it's therefore going to impact B-cell depletion.

So I think it's possible that we may need to dose a little higher in these very severe pMN patients like the patients that we're currently enrolling in PrisMN. And that's where the real unmet need is, and that's the group that we're focusing on for further development. So I think that's just a super important concept. I think when it comes to finding the right dose, there's what you can measure and what you can't measure when it comes to B cells. We've developed the most sensitive B-cell assay that we'll be sharing a little bit more detail on as we start to give some of the readouts this year. But I think what's equally important is what happens to some of the important clinical endpoints like the PLA2R antibody level. So it's possible that you can get to a dose that looks great on B-cell depletion, but actually a subsequent dose may be preferable when it comes to some of the immune biomarkers.

So we're studying all of that in the ongoing studies. We want to make sure that we choose the right dose to go forward. And so far, safety and tolerability has not been a limitation. So we feel that it's important to do this kind of dose range finding in the diseases of interest. But then we believe that may be applicable to other diseases as well as we kind of focus on really understanding the PK/PD we think we may be able to apply that to other diseases outside of the diseases that we're currently evaluating.

Anything you'd add there, Edgar?

No, that was really complete.

And our next question will come from the line of Colleen Kusy from Baird.

It's Nick on for Colleen. Congrats on the progress. First, I just want to start out if you could just lay out some expectations on what we can see with these initial readouts. And then secondly, just given the expansion of UPLIZNA development such as in CIDP, autoimmune hepatitis, does this give you an idea of where to possibly move next with Budo?

Great. So in terms of the upcoming readouts, I'll share that and then tight team with Edgar again here becoming a pattern to talk about UPLIZNA and some of those indications. So for ITP, we previously guided to having data in the second half of '26. We've now disclosed that we have a June presentation, which will predominantly focus on safety, B cells and platelet response in the low-dose cohort at the 3- to 6-month follow-up time point.

As I mentioned, we'll also be sharing details about our high-sensitivity B-cell assay that we're using across all of our studies. But those patients will continue to be followed per protocol. They'll get a second dose around 6 months. And then we'll also have data from the higher dose cohorts as we go through the year and into the second half. So I think you can see what you can expect is this upcoming presentation in June, followed by subsequent disclosures as the data set matures and as we conclude enrollment in some of those higher dose cohorts.

And for pMN, we're super excited about the PrisMN study. We announced that we dosed our first patient in November. So as we think about the second half of the year, we have almost completed enrollment in the first cohort, and we're seeing enrollment accelerate as we get some of our sites up and running. And we anticipate that the first cohort will be at the 3- to 6-month time point at the time that we share some of the initial data. But like everything else, we'll continue to look and allow the data to mature and look at the complete response endpoint as more patients start to get to that 12-month time point, which is really the important -- that's the start of when you can start to see the complete response rate.

But you can see proteinuria trends earlier, and we'll be sharing B cells, PLA2R and proteinuria from that first cohort later this year. So really, I think, a very exciting kind of catalyst calendar as we think about some of these upcoming readouts, and we're excited to progress.

Yes. I think inebilizumab's expansion into other autoimmune diseases is really a further testimony to the potential for CD19 targeting in autoimmune disease. So you can envision that CD19 targeting would be efficacious in a variety of B-cell-driven autoimmune diseases in CIDP and AH makes sense. In contrast to UPLIZNA, we have higher picomolar affinity for CD19, and we do have our subcutaneous formulation under development. I think what we'll do is we'll take all the data that are coming out of our current studies as well as our future planned study in patients in subcutaneous formulation to make a decision about next indications we want to pursue.

And our next question comes from the line of Julian Harrison from BTIG.

Across the 3 declared indications so far for Budo, pMN, ITP and lupus, I'm wondering if you have a good sense for how much CD20 targeted therapies are currently utilized? And do you expect that use captures the total TAM for Budo most likely? Or do you maybe expect Budo to likely grow those market categories as well?

Yes, that's a great question, Julian. And I'll pass that one over to Perrin, who is really following the commercial and competitive landscape here most closely. Perrin?

Yes. Thanks, Julian. So I think if we focus in on pMN and ITP, which we talked a bit about earlier, rituximab is used in both of those indications off-label. I think it meets some of the needs of patients. Some patients do achieve a response or remission, but ultimately are not served long term with these therapies. And I think that's where we think budoprutug can come in. Looking at the breadth of expression with CD19, we think particularly as it relates to pMN, which is an IgG4-driven disease, we think hitting those early precursor cells and then also the plasmablasts and many of the plasma cells is really going to give us a distinct advantage over the CD20 approaches.

And I think the same is true in ITP. Edgar took you through where taking the spleen of those ITP patients who are resistant or have failed rituximab, you see really the expansion B-cell cohorts are that CD19 positive population. And so we think Vutaprutu has the opportunity to really deliver great results for patients, not only in the front line, but perhaps also in those CD20 failure patients.

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

One for me on the pMN competitive landscape. With the PrisMN data coming up, I guess I'm trying to understand what are you hoping to see from Budo that might help it compare, contrast versus other mechanisms? So we have APRIL/BAFF, CD38, a number of other mechanisms advancing in pMN. But maybe you could talk a little bit more about how you see the market evolving and the segmentation, but also how does Budo kind of slot in versus some of these other mechanisms? And then just lastly, I believe IgAN has a Phase II UPLIZNA study in SLE with lupus nephritis as well. Anything else that you could articulate to clarify on kind of differentiation there?

Yes. Another great question for Perrin.

Yes. So as we discussed today, particularly in pMN, no approved therapies, PNIs, rituximab commonly used off label. And I think this underscores the unmet need there. Looking ahead in pMN, we think the next key competitive inflection point is really the upcoming obinutuzumab MAJESTY readout at ERA. We expect these data to be positive, but anticipate only an incremental improvement over what's been historically observed with rituximab. And this is really supported by the Phase III data from a Chinese study of a next-generation CD20 agent, which was presented at ASN last year, which showed just that modestly higher complete renal remission rates compared to what had been seen with rituximab previously. And Edgar, do you want to comment a little bit about the APRIL/BAFF mechanism there?

Yes. So we think CD19 is really the best target for pMN for all the reasons that we've mentioned in the IgG4 producing plasmablasts, which are squarely expressers of CD19. Povetacicept is released a little bit of data in pMN. As a BAFF/APRIL inhibitor really addresses more of the downstream pathophysiology rather than the root cause of disease, which would be targeted by a CD19 therapy. So we think that budoprutug has the potential to have more deeper, more durable responses without the need for chronic regular dosing, such as monthly dosing that povetacicept is studied.

And our next question will come from the line of Danielle Brill from Truist.

Maybe for Dr Jayne, if I may. Can you comment on the role and prevalence of double negative and CD20-negative CD19-positive B cells across ITP, SLE and pMN. I'm wondering where you believe Budo's activity against these populations creates the greatest differentiation versus other B-cell-directed approaches? And maybe as a follow-up to that, to what extent do you believe Roche's obinutuzumab and the greater potency observed as a CD agent overcomes the limitations that have historically been observed with rituximab? And also where do the gaps remain?

Thank you for the question. The term double-negative B cells usually defines a subset of B cells that lack CD27 and CD5 surface markers. They retain CD19 and CD20. So they've been identified because they seem to be particularly important in the pathogenesis of lupus and there's been relatively less work done in the other indications under discussion. And I mentioned them because they would be a suitable target for CD19 therapy. They're also clearly a target for CD20. And they are a measurable circulating representation, if you like, of pathogenic B cells.

Your second question related to obinutuzumab. And I think this was touched on a little bit in my presentation. There's no doubt obinutuzumab is achieving better responses in the periphery and better responses in lymph nodes in terms of B-cell depletion. I think the real problem is that obinutuzumab remains restricted to CD20 and is not affecting the CD20 negative plasmablasts or plasma cells. And there's certainly data from rituximab, although less at the moment from obinutuzumab, is the CD20 negative cells that persist and drive relapse in these disorders. So I think the advantage here of CD19 is really the broader cell coverage, including plasmablasts and plasma cells. And the key question is whether the broader coverage CD19 yet to that state of follicular disruption that we referred to, which we think is consistent with long-term treatment-free remission, which is really the goal in autoimmunity. And we know CD20 negative cells are a component of what you have to do to get there.

And our next question will come from the line of Thomas Smith from Leerink Partners.

This is Brian on for Tom. I appreciate you guys hosting the event, and thanks for all the nice updates here. Just 2 questions from us. Maybe first on the SLE study in China. Do you have a sense of how we should think about the similarities or differences of the patient population of lupus patients enrolled in China versus your ongoing global study? And second, for the Phase II pMN study, we noticed some minor changes to eligibility on ct.gov related to maximum age and eGFR inclusion criteria. Would you be able to comment on these changes? And I guess, how enrollment is progressing to date?

Yes, Brian, I can take the first and last one and then let Edgar address the patient execution criteria. So for China, I think you can see today that we've shared the design for both the global study and the China study. Both are very, very complementary. In SLE, I think it's particularly important in terms of the genetic background for these patients, particularly with regard to safety. And we think the most important thing that we can achieve across both studies is really understanding the dose that can achieve B-cell depletion in a well-tolerated manner in these kind of fragile SLE patients. You can see from other modalities that often it's the SLE patient population that are most prone to some of the short-term safety and tolerability issues.

So what was the primary goal for us was to really make sure we were able to evaluate a number of doses from a safety and a tolerability perspective as well as understand the dose that can achieve deep B-cell depletion in this SLE patient population. I mean, obviously, we'd love to see some trends on efficacy as well, but that was kind of very much a secondary endpoint here. So we think both studies are going to be super complementary in that. And we'll really address the question you're getting at is whether there are ethnic differences in those patients when it comes to PK/PD and the safety and tolerability piece. So we'll be, I think, very excited to see the data and the totality of the data across both studies because I think both will be integrated and very, very important.

In terms of eligibility, Edgar, do you want to speak to that?

Regarding the pMN study, as Aoife mentioned, enrollment is on track. We're close to completing enrollment in the first dose cohort. We did broaden the inclusion criteria with a higher age exclusion as well as lower the eGFR exclusion really to capture a broader variety of patients that we may want to study going into Phase III.

Our next question will come from the line of Leland Gershell from Oppenheimer.

A couple of questions from us, first for the company. Given the potential for very deep B-cell depletion with Budo, I guess, do you ultimately envision this is more of a sort of a finite reset regimen with retreatment guided by biomarkers or a true chronic maintenance therapy? And is there any -- I know your early clinical data is fairly limited, but any observations you can draw there about relapse kinetics and retreatment intervals? And then I have a question for Dr. Jayne.

I think it's too early to tell from the data. We are certainly looking to have a 1 or 2-and-done type approach where 1 or 2 cycles may be sufficient to have a long-lasting remission. We've already seen from our initial pMN study that 1 or 2 cycles of budoprutug led to durable remission at least up to 3 years in our pMN patients, and we certainly hope to recapitulate that in our Phase II study. So I think that really goes to the heart of our exploration of dose regimen. It also may depend upon indications. Some indications may be more amenable to a reset that's at least to a drug-free remission than others. But we're certainly going to be learning from all of our indications and dose regimens together to come up with an idea of a dose regimen for our registrational studies.

And the nice thing to add to that is that even if a patient does require chronic administration of therapy, that can be achieved with a monoclonal antibody. Depending on the benefit risk for that individual patient, that's something certainly that's in scope and not precluded unlike some of the other kind of more complex modalities.

So I'll now open the floor to your next question for Dr. Jayne.

Great. And just want to ask your opinion, obviously, the guidelines recommend Rituxan and other CD20 antibodies for pMN, but there's remission rates that are substantial, meaningful nonresponders and on obinutuzumab looks lined up to be the first actual approval here, we've seen Phase III data. So I guess what would you, Dr. Jayne, like to see out of Budo's development that could potentially put that candidate as a first-line therapy in pMN?

So the common result with rituximab, you get a response in terms of reduction in proteinuria to sub-nephrotic levels, but you much less commonly get what I would call a complete ring response, response well below 0.5 grams -- milligram -- per milligram. So I think the first thing that I'd be looking for with Budo would be the depth of the proteinuric response. Clearly, you're going to look at impact on circulating autoantibodies such as anti-PLA2R. These do not correlate perfectly with clinical response.

But because this is a B-cell targeted therapy, you're going to get an earlier readout on autoantibody levels. So I'll be looking within the first 6 months at clearance of pathogenic antibodies. As I alluded to with rituximab, we often don't see complete clearance of pathogenic antibodies.

And our next question will come from the line of Matt Phipps from William Blair.

Thanks for all the additional disclosures this morning around the development. I was wondering, as you're looking at the subcu development, do you think there will be a need or do you plan to explore any kind of loading dose followed by maintenance, so maybe 2 doses upfront and then as a maintenance. And then for any of these ongoing studies, do you think you'll be able to get any lymph node biopsies to try to look at that deeper level B-cell depletion?

Thanks, Matt. I think as I mentioned earlier, I think it's a little too early for us to identify the ideal regimen. But we do look to the CD20. I mean they're B-cell depleters. We can learn from their development. And there, you can see that particularly in the case of Kesimpta, there is this kind of concept of a number of doses in quick succession to deplete the initial B-cell count and then the maintenance of the monthly subcu at a low dose to kind of maintain B-cell suppression in the MS indication.

So certainly, that is one model that's likely viable. I think really understanding some of the modeling, some of the CD19 and CD20 kinetics that we'll evaluate at the full B-cell depleting dose as well as some of the indications that we plan to pursue will help us identify what the ideal dosing regimen looks like. So more to come for sure on that.

Yes. Regarding lymph nodal biopsies, we certainly aim to get tissue from some of our ongoing studies to look at the B-cell depletion. In respect to the earlier question about double-negative B cells, our high-sensitive B-cell assay is also multidimensional from a flow cytometry standpoint. We'll be interrogating for disappearance and reemergence of those types of populations through the use of CD27 and CD11c.

Our next question will come from the line of Mayank Mamtani from B. Riley Securities.

I appreciate the helpful detail here. So maybe just building on the prior question on landscape positioning. And as we look into the ERA data set for MAJESTY. If you could talk to the clinical parameters that are relevant to follow even not just for CD20, but also BAFF/APRIL. So we understand a bit more on the CD19-mediated impact on long-lived plasma cells, both from a safety and immune reset standpoint. And relatedly, would be helpful to hear level of PLA2R remission that makes sense for you to see here that could inform a potentially expedited path to a pivotal Phase III program.

Yes. So I mean, I think what's most important in pMN is the approvable endpoint, which is the complete renal response that we understand from the MAJESTY study is a 24-month endpoint. We know that, that's positive. We haven't seen the proportion of patients that achieve that endpoint. And we also don't know at this point how much granularity we'll get with the upcoming presentation on some of the earlier time points that in the short term are going to be more meaningful for us as we kind of start to accrue and mature our data set.

So we'll be watching that presentation. We have a team on the ground at ERA. And I think once we see some of those data, we'll be able to better answer your question around kind of some of the early time points of PLA2R and the proteinuria trends and how much data we have on each of those endpoints as we go through this year. But an exciting time for pMN for sure, going from a space with nothing approved to now a number of products in the pipeline. So certainly good for patients.

Great. Wonderful Q&A session. I know there's a lot happening this morning. So and it's Cinco de Mayo. So thanks so much, everyone, for joining us, and we look forward to having future spotlight events as we go through the year and keep everyone updated on our 2 very exciting programs. Thank you, operator.

Thank you for your participation in today's conference. This does conclude the program. You may now disconnect. Everyone, have a great day.