AnaptysBio, Inc. (ANAB) Earnings Call Transcript & Summary

Good day, and thank you for standing by. Welcome to the Anaptys PD-1 Agonist Rosnilimab R&D Event Webcast. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to Dan Faga, President and Chief Executive Officer of Anaptys.

Welcome, everyone. We are excited to host today's event focused on rosnilimab, our internally discovered PD-1 agonist. This presentation will contain statements that are forward looking. We're going to review what are massive opportunities for rosnilimab with a best-in-class profile in rheumatoid arthritis, where there is proof-of-concept for this mechanism and announcing today a first-in-class study in ulcerative colitis. Joining me from Anaptys are Dr. Paul Lizzul, our Chief Medical Officer; Dr. Martin Dahl, our SVP of Research; and Dr. Cailin Sibley, our VP, Translational Medicine. Also, we've had 2 distinguished physicians prerecord their sessions. Dr. Jonathan Graf, Professor of Medicine at the University of California, San Francisco; and Dr. Bruce Sands, Professor and Chief of Gastroenterology at the Icahn School of Medicine at Mount Sinai. We'll conclude today's presentation with a Q&A session for analysts with the Anaptys management team. Anaptys is developing a portfolio of targeted immune cell modulators with broad potential in many systemic autoimmune and inflammatory diseases in the areas including rheumatology, gastroenterology and dermatology. We are well capitalized with 2023 year-end cash guidance of up to $395 million and runway through year-end 2026, allowing us to execute an optimal multi-year development plan and ongoing research as leaders paving the path in this exciting field. Our portfolio includes 2 clinical stage best-in-class checkpoint agonists. Today's focus is on rosnilimab, which can potentially change the treatment paradigm for patients in both RA and UC, where there is, unfortunately, a significant unmet need. Our RA Phase IIb trial has already initiated with top line data expected by mid-2025. And the UC Phase II trial, which we'll initiate this fourth quarter, and we are guiding to top line data by the first half of 2026. Beyond rosnilimab, we're also developing ANB032, our BTLA agonist, enrolling patients in a Phase IIb trial for atopic dermatitis with top line data expected by year-end 2024. And we also expect to share more information about our CD122 program, ANB033 next year with an IND submission on track for the first half of 2024. RA and UC are the first 2 trials we have initiated for rosnilimab since we announced the strategic transition of our company. These diseases can be characterized in part by the significant prevalence of PD-1 positive T cells in both the inflamed tissue and periphery. While the decision to invest in the development is multi-factorial, this is just a simple pre-record PD-1 agonist development. On the left, in the immunohistochemistry stains of the cytopathology in RA and UC, they are represented by synovial tissue in the joint and lamina propria in colon. In the first column, you can see a dense infiltrated T cells, which are mostly PD-1 positive as highlighted in the second column. This is summarized in the chart on the right. Here, at least 80% of these are PD-1 positive T cells in RA, and 40% are PD-1 positive T cells in UC. We'll get into more specifics later in the presentation, but this data is in contrast to what has been characterized in alopecia areata, a more localized inflammatory disease, where we did not observe sufficient efficacy in a small Phase IIa study earlier this year. PD-1 positive T cells were essentially undetectable at the hair follicle in the chronic alopecia areata patients we studied. This is more akin to what you would expect to see in a healthy individual. Unlike in alopecia, in systemic inflammatory diseases like RA and like UC, there is a multi-fold enrichment of PD-1 positive T cells, not only in the tissue but also in the periphery, i.e., the blood as compared to healthy controls. PD-1 checkpoint receptors present as a marker and regulator of activated T cells. I know you're familiar with PD-1 antagonists developed as cancer treatments. These antibodies block the ability of PD-1 on T cell to bind with its natural ligand, PD-L1 on an opposing cell. In the context of cancer, this allows the immune cell to operate unchecked, thereby releasing the brakes on immune cells and remain activated and further proliferate. Rosnilimab, on the other hand, is a best-in-class agonist that specifically targets the PD-1 receptor at a location proximal to the immune cell membrane. In the context of autoimmune and inflammatory diseases, rosnilimab hits the brakes on runaway inflammation to restore immune balance by bringing T cell composition to a healthy or less activated state. Rosnilimab accomplishes this via 3 distinct mechanisms of action to deplete PD-1 high effector T cells to deplete PD-1 high Tfh and Tph cells, which together, these PD-1 high T cells are the most pathogenic T cells. And third, rosnilimab agonizes PD-1 intermediate T cells to downregulate T cell activity. These 3 MOAs reduce PD-1 high and PD-1 intermediate cells in both the inflamed tissue and periphery, which is depicted on this slide. Rosnilimab's reduction of PD-1 positive effector T cells through depletion or reduction in their activation stats through agonism through as a direct reduction in T cell migration from the periphery into inflamed tissue, reduces further T cell proliferation and reduces inflammatory cytokine secretion. Also, rosnilimab's reduction of PD-1 positive Tfh and Tph cells leads to lower auto-antibody levels implicated in disease. There are many classes of relevant approved therapeutics, particularly in RA and UC, where their MOAs only target a subset of these immunological outcomes driven by rosnilimab. These include S1Ps and alpha-4/beta-7s, which reduce migration of T cell into inflamed tissue. And TNFs or IL-6s, which are only single cytokine blockers. That said, given rosnilimab's targeted focus to deplete and agonize only PD-1 positive T cells, we believe we will avoid liabilities associated with overly broad JAKs, lymphocyte depleters and B cell depleters. For all these reasons, we believe rosnilimab's impacted inflamed tissue and periphery has potential to deliver differentiated efficacy with a safe profile to patients with heterogeneous diseases, including RA and UC. Both moderate to severe RA and UC are well-established large markets. In the U.S. alone, a significant number of patients, 0.5 million in RA, over 100,000 in UC progressed post-treatment with biologics such as TNFs or other advanced therapies. For RA, only 20% to 35% of patients achieved ACR50, with 1/4 of these patients ultimately cycling through all available treatment options. And it's the same for UC, only 25% to 30% of patients achieved remission on the modified Mayo score, in that first 3 months induction phase, and it gets worse, 1/3 to 1/2 of these patients relapse within a year. There is significant room for a new class of biologics in both of these diseases to differentiate in patients already experienced in taking biologic therapies and who are looking for better options in both RA and UC. Finally, we believe the data and translational insights from our Phase II studies will inform a range of additional systemic inflammatory diseases we may be able to pursue with rosnilimab. In the remainder of today's presentation, we'll reaffirm 4 points about rosnilimab. First, it targets only PD-1 positive cells in both inflamed tissue and the periphery, which broadly impact pathogenic drivers of heterogeneous and systemic autoimmune and inflammatory diseases. Second, it's best-in-class. Third, our clinical development plan in RA and UC, is backed by robust translational and human safety data. And fourth, we are off to the races as we execute our Phase IIb trial for RA and initiate the Phase II trial for UC later this quarter. Now for Dr. Martin Dahl, our SVP of Research.

Thank you, Dan. In this section, I'm going to walk through PD-1 biology. Why PD-1 agonism is an exciting approach for the treatment of inflammatory diseases. And rosnilimab's best-in-class profile to achieve optimal depletion and agonism. PD-1 is expressed on activated T cells and is a key co-inhibitory node in immune regulation. PD-1 positive T cells represent primarily 2 pathogenically distinct T cell subtypes in the context of autoimmune and inflammatory diseases. PD-1 expressing T effector cells reside primarily in inflamed tissue. And throughout this presentation, you'll see them show up as the red cells being here. T effector cells express PD-1 at levels that correlate with their activation state with intermediate to high levels of PD-1. These cells secrete inflammatory cytokines, cause tissue damage and perpetuate the inflammatory cycle. T follicular helper, Tfh and T peripheral helper Tph cells, which show up in this presentation as cells in purple are defined by high levels of PD-1. Tfh cells are primarily in the follicles and can migrate through the periphery and into inflamed tissue, where they referred to as Tph cells. One of their key roles is to orchestrate B cell recruitment, maturation and the generation of auto-antibody secreting plasma cells. They do this by secreting CXCL13 and IL-21. These PD-1 high T cells, both the activated T effectors and the Tfh and Tph cells are the most pathogenic T cells and represent targets for depletion to reduce inflammation and tissue damage. How does rosnilimab's unique mechanism of action target these PD-1 expressing T cells. As Dan mentioned, rosnilimab has 3 distinct mechanisms. In the top and middle rows, rosnilimab targets the PD-1 high and PD-1 intermediate effector T cells that are proliferating rapidly and secreting high levels of inflammatory cytokines. The combined mechanism of depleting PD-1 high expressing T effector cells and agonizing the PD-1 intermediate cells leads to the reduction of T cell activation, migration, proliferation and cytokine secretion. In the bottom row, rosnilimab depletes PD-1 high Tfh and Tph cells, which are responsible for orchestrating B cell maturation and generation of auto-antibody secreting cells that contribute to autoimmunity. Depleting PD-1 high T cells and agonizing PD-1 intermediate cells will address multiple immunological and clinically validated drivers of disease. In healthy and even disease patients, most T cells are activated and therefore, not expressing PD-1. Rosnilimab specifically targets only the PD-1 positive T cells. On the lower left, we're showing the peripheral T cells from a healthy donor dosed with rosnilimab. The plot on the left is before dosing. There's a small percentage of PD-1 high T cells in the red gate and a minority of PD-1 intermediate T cells in the yellow gate. About 80% of the T cells reside in the blue gate, which are PD-1-negative. Rosnilimab doesn't bind to these cells. 15 days after dosing rosnilimab, all the PD-1 high T cells are depleted, and the remaining PD-1 intermediate T cells are agonized, reducing numbers and activation state of the remaining cells. As you can see in the stacked bar chart, rosnilimab depletes the PD-1 high T cells and reduces the number of PD-1 intermediate T cells. It does this without significant reduction in overall T cell counts. This brings the T cell composition back to a less activated state restoring immune balance. T cells are activated by dual signaling through TCR stimulation and co-stimulation by CD28. PD-1 provides a co-inhibitory immune suppressive signal upon binding to its ligand, PD-L1, on an opposing cell. This PD-1 agonistic signal reduces T cell activity. Rosnilimab binds to PD-1 and simultaneously anchors to an Fc receptor on opposing cell, facilitating cross-linking without disrupting natural PD-L1 engagements. Earlier this year, a paper was published by Tasuku Honjo's Group. He was awarded the Nobel Prize in 2018 for identifying PD-1. In this paper, they matched 81 antibodies to different binding epitopes on PD-1. Antibodies that generally bound to the membrane distal region of PD-1, as indicated in red, largely antagonized PD-L1 binding to PD-1 and induced IL-2 in T cells, just as observed by the PD-1 antagonist antibodies using oncology to release the brakes. They also found that antibodies, which found more membrane proximal inhibited IL-2 activity through PD-1 agonism to hit the brakes, and they identified an optimal epitope, epitope 7 that most potently agonized PD-1. Epitope 7 is where rosnilimab binds. We utilized PD-1 mutation mapping to identify this footprint as indicated in blue. In contrast, Lilly's PD-1 agonist binds to a membrane distal region of PD-1, shown in yellow. To paraphrase a key point from Tasuku Honjo's pivotal paper, a shared feature of PD-1 agonistic antibodies is both recognition of a membrane proximal binding epitope and simultaneous Fc receptor supported cross-linking of PD-1. These characteristics having a membrane proximal binding epitope maximal Fc receptor binding affinity and other PD-1 binding properties such as optimal affinity and binding footprint, drive the potency of the PD-1 agonist, to deplete PD-1 high T cells and reduce the number and activity of PD-1 intermediate cells through agonism. Rosnilimab checks all these boxes and will show that Lilly's PD-1 agonist is less potent, in part because it binds to a more membrane distal epitope. On the next slide, we've characterized rosnilimab's best-in-class activity using 2 completely separate assays, one that specifically assesses depletion by co-culturing PD-1 positive T cells with NK cells, and another that specifically assesses agonism by activating T cells in the presence of only dendritic cells. On the left, in blue, rosnilimab is a potent depleter of PD-1-positive T cells in the presence of only NK cells. While Lilly's PD-1 agonist also has activity in orange, it reaches a plateau at about 1 nanomolar, and doesn't deplete more deeply despite increasing concentrations of drug. On the right, we're measuring only the agonism properties of rosnilimab in the absence of cell types that would mediate depletion, activating T cells in the presence of only dendritic cell. Rosnilimab in blue potently reduces proliferation and reaches a deep level of inhibition, while our competitor in orange has limited activity to reduce proliferation and again demonstrates a plateau and activity. These assays demonstrate differentiated depletion and agonistic activity of rosnilimab compared to Lilly's PD-1 agonist. We're excited about having a potent and differentiated PD-1 agonist. PD-1 is expressed preferentially activated T effector and Tfh and Tph cells mediating autoimmune pathology. Rosnilimab targets these cells with optimized dual mechanisms of action, depletion and agonism in both inflamed tissue and periphery to restore the T cell composition to a less activated state. Now it's my pleasure to introduce Dr. Jonathan Graf from the University of California, San Francisco, who will speak about rheumatoid arthritis pathology and introduce how treatment with the PD-1 agonist could lead to differentiated outcomes for patients where standard-of-care is insufficient.

Thank you so much, Martin. The topic really I want to speak about is the current treatment landscape for RA therapeutics in the year 2023. Our current therapeutic approach to treating RA really has evolved over the last couple of decades to become one that's considered a treat-to-target approach, where we really are targeting low disease activity or better. And what we'll often do when we see a patient with early rheumatoid arthritis is, we'll start a conventional synthetic DMARD, like methotrexate with the goal to retard radiographic progression and reduce signs and symptoms of the disease. But then we'll actually bring a patient back and assess whether or not we've achieved our target of low disease activity or better. And if that hasn't been achieved, we'll often add on a biological DMARD, usually the first line biological DMARDs or anti-TNF agents or we'll add a combination of conventional synthetic DMARDs, and then bring patients back in subsequent months to see if we've been able to achieve our disease activity target, again, of low disease activity or better. And if the disease continues to remain active, we'll gradually ascend this pyramid of RA therapeutics, that's been growing over the last couple of decades, again, with the subsequent attempts to achieve low disease activity or better. But even with this treat-to-target strategy, our ideal goal of achieving remission in our patients is really accomplished in less than 60% of our patients, no matter how many biological agents we have available to us. That list of biological agents has been growing in recent years, but we don't really know which ones provide the best treatments for which of our patients. And so, Jim O'Dell who's a noted RA expert, has this RA wheel of therapy that will sometimes spin to try to figure out what biological agent to give to a patient who hasn't achieved their disease activity target. One of the reasons we find ourselves doing this is because RA is a heterogeneous disease. There is no standard biomarker with which we can use to predict which therapy will be best for which patient. And so, the RA therapeutic landscape as it currently exists is often riddled with trial and error. And this can lead to experience cycling through therapies. And of course, there's an ultimate delay even if we're lucky enough to reach [Technical Difficulty] and again, these can include our conventional and synthetic DMARDs, our biological DMARDs like anti-TNFs or T cell co-stimulation blockers, anticytokine therapies that are targeted against interleukin-6, for example, B cell depleting therapies and even targeted synthetic DMARDs like the most recent class of JAK inhibitors. We have what looks like a very full therapeutic landscape in front of us. But in reality, for many patients, especially those patients that I said, over 40% who are not in remission, it actually looks more like a therapeutic desert. And to sort of make this point, I want to point out a study from France that was published just in the last year. That's a real world study, not a clinical trial. The objective of the study was really to evaluate the remission rate and the maintenance of remission in patients who had RAs after 7 years of real world follow-up in an observational cohort. This cohort took place during a period that encompassed the emergence of treat-to-target therapies and also encompass the development of this biological DMARD landscape that I just talked about here. And what you'll see is over the course of 7, 8 years of patient treatment, even with the availability of these additional DMARDs that came on the market, more than 40% of patients still found themselves not to be in remission. Another way you can look at this is, you can look at the sort of holy grail of biological therapies, which we would probably consider to be the anti-TNF therapies. And in particular, the most popular of these, I think all of us would consider to be adalimumab. And if you look at the ability of patients who start adalimumab to stay on adalimumab over the course again of 8 years, and this is another study from a different country published within the last few years. What you'll notice, again, on the left, looking at adalimumab is that after about 6 months of therapy, the response rates, particularly the ACR20 response rates in this real world cohort mirror what you see in a clinical trial, about 80%. But after about 8 years of therapy on adalimumab, that response rate is down to about 30%. Emphasizing the fact that the real world is not a clinical trial. RA is a lifelong disease that most people have to live with for decades after they're diagnosed, usually in their 30s or their 40s. And in fact, if you look at the number of people who are still on adalimumab after 8 years of follow-up, only about 38% of patients who start adalimumab are still on that therapy after 8 years, again, highlighting the need for additional therapies to treat this lifelong disease. Now, one of the reasons this is true is that our current biological DMARDs don't actually cure rheumatoid arthritis. And so despite the fact that patients will often live for 4 or 5 or even more decades of life with this disease, all the best we can do is to temper their symptoms and hopefully prevent complications -- long-term complications from unbridled inflammatory and -- this inflammatory and autoimmune based disease. In fact, and sort of again, to highlight this point, if you look at patients who are in durable remissions and these are data published from the ARCTIC REWIND TNF trial, they are hot off the press just in the last few weeks. So this is looking at patients who did achieve remission and had maintained remission for more than a year, okay? The decision for this particular trial was to either randomize patients to taper their TNF therapy off or keep them on their current stable TNF dose. And then it followed patients for the subsequent year to see who flared. And in fact, in these well-controlled patients who discontinued their TNF therapy who tapered it off, almost 2/3s of them flared as defined by the study compared to almost nobody who continued on their TNF therapy. This emphasizes the fact that RA is a chronic lifelong disease, whose symptoms are kept in check and even the best controlled patients with our drugs. But if we ever stop the drugs, it's a reminder that the disease has never really gone away. And one of the reasons again for this is the fact that the therapies that we have to treat RA patients today at downstream to control signs and symptoms usually cytokine-driven type symptoms of the disease. And while this can be effective in a lot of patients, and while it does slow radiographic progression and other long-term complications of the disease, it ultimately doesn't reset the immune balance back to normal. One potential pathway that has been looked at, that could potentially do that is the PD-1, PD-1 ligand pathway, because this is a central nodal point in regulating the most proximal events in autoimmunity, particularly those that lead to T cell activation, presumably against pathologic auto-antigens like citrullinated peptides. Activating on this very proximal portion of the pathway by down-regulating activated T cells or preventing them from becoming activated in the first place, there is the ability potentially to affect disease much farther downstream that includes many known targets of current therapeutics. For example, TNF alpha and interleukin-1 sit downstream of here. The IL-6 pathway that we know we have targeted therapeutics for sits downstream of all of these events as well. B cell activation and plasma cell development can be affected as well. And in addition, there are other cytokines that drive the pathology of disease, such as GM-CSF that use the JAK/STAT signaling pathways for which we now also know we have therapeutics. And so there's the potential to block these upstream events and by consequence, have positive effects on myriad downstream inflammatory pathways, regardless of which one is the most pathologic for any given patient as well. And as a clinical proof-of-concept, PD-1 agonist class has already been shown in published clinical trials to have compelling data. So where does that leave us today? Well, there are many unmet needs in RA. There are still a sizable number of patients who are not at their RA disease activity targets. These are specialty targets that we hopefully strive for to achieve remission or even better in our patients. And I think anybody who has an active disease like RA would hope that their doctor is attempting to achieve full remission. And there's a need, as I just argued, to reset the immune system environment at its most proximal level so that treatment efficacy number one doesn't wane. And number two, offers the potential to work in all RA patients regardless of disease heterogeneity. We don't know which one of our targeted current therapies works for which patients. But if we have a drug that can potentially block the most proximal pathways, it may not even matter in the first place. And one analogy I'll leave you with is really to think about the environment in which one lives. If you move to Phoenix, you'll certainly have to keep the air conditioning running all summer in order to keep your house cool. And that's fine and dandy as long as your air conditioner works. But if the air conditioning stops working, you're in real trouble and your house is going to heat up fast and you're going to get very, very sick. On the other hand, you can move to, say, a place like San Diego, where the climate outside is very tempered and often controls the climate inside. Electricity bills will be much less as a result because you won't need air conditioning in the first place. And I think that's what the Holy Grail is for those of us hoping to treat and potentially even cure RA in our patients. So with that, I'll turn to Cailin, who will be speaking to you now about the details of Anaptys' current PD-1 program.

Thank you, Jon. Dr. Graf provided a compelling overview of the challenges in the current RA standard-of-care and perspective on how to break through the efficacy ceiling with PD-1 targeted therapies. I'm now going to show additional translational and clinical data supporting the potential of rosnilimab to result in differentiated outcomes for patients. As Dr. Graf discussed, T cell activation is an essential upstream node in the initiation of RA. In RA patients, when naive T cells interact with antigen-presenting cells in the lymph node, they become activated and differentiate into PD-1 positive T effector and Tfh cells is visualized in red and purple. T effector cells proliferate and migrate into the synovial tissues where they secrete cytokines that cause synovial inflammation and activation of macrophages and fibroblasts. Ultimately, this results in damage and inflammation within the joint. PD-1 high, Tph cell seen here purple are present in large numbers in the synovium. They drive B cell maturation into plasma cells. T cells generate autoantibodies, including anti-CCP antibodies, large immune complexes known as rheumatoid effector. Rosnilimab impacts multiple pathways, either directly or through downstream effects, which overlaps with mechanisms of approved therapies in RA further validating our approach. As rheumatologist, it's very exciting to consider that PD-1 agonist has the potential to impact all the major immune drivers of RA, which may be key to breaking through the efficacy ceiling that has been observed in other approved therapeutic classes. Now let's focus on the PD-1 high Tph cells, represented here in purple. I'm going to talk through 2 different places where Tph cells are elevated, the periphery and synovium and how they drive disease through pathogenic cytokine production. Dan showed earlier that PD-1 positive cells are upregulated in synovial choice. Over 80% of the T cells that accumulate in the synovium are PD-1 positive, and this is seen across the range of disease stages and severity. Tph cells with high levels of expression of PD-1 are a subset of this population. In the upper left graph, PD-1 high Tph cells in the peripheral blood are increased in RA patients compared to healthy controls. This look like a small percent, remember that this relatively small number of cells are the most pathogenic. Importantly, shown in the lower left graph, these cells are greatly increasing the synovium of RA patients when compared to osteoarthritis, a non-inflammatory disease control where they're essentially absent. Tph cell secrete IL-21 and CXCL13 which drive auto-antibody production, a defining feature of RA. Eliminating these PD-1 high Tph cells by depletion is an important part of being able to drive deeper responses in RA patients. The molecular drivers of RA are diverse. Shown on the slide are data from the accelerated medicines project. This is a very large seminal study between pharma, the NIH, active emissions in the FDA, where the goal is in great detail to molecular phenotype tissues from patients with rheumatoid arthritis. Represented here are single cell RNA seq data from synovial joints. One can appreciate the heterogeneity both within the disease on the left and between patients on the right. This is a known barrier to better treatment outcomes in RA. Today's approved therapies with narrow mechanisms of actions are unable to adequately treat most patients, which leads to inadequate standard-of-care. The approved class that comes closest to addressing the heterogeneity is the JAK class, which shows better efficacy than single cytokine targeted biologics, however, is limited by safety concerns given their non-specific mechanism of action. PD-1 agonist uniquely have the potential to address the heterogeneity by impacting all the major cell drivers of rheumatoid arthritis in a safer manner. Perhaps the most compelling data to-date for understanding the role of the PD-1 pathway within RA is a clinical proof-of-concept data from another PD-1 agonist. The primary endpoint in this trial was CDAI, which is the clinical measurement of rheumatoid arthritis activity. In the upper panel, there is convincing improvement in the score at both dose levels is visualized in blue. Importantly, at week 12, these data look quite similar in those patients who are biologic experienced versus those that are naive. Significant unmet need remains after initial biologic failure. The PD-1 agonist class is particularly well suited to address it. This is not achieved by other classes of approved therapies, which may be because PD-1 positive T cells remain elevated and drive disease in biologic experienced patients. Those patients who achieved low disease activity through week 14 continued on the study and sustained their responses through week 24. These data are exciting, but we believe we can do better. Further supporting our differentiation, we profiled rosnilimab relative to Lilly in depletion and agonism assays. Here, we are looking at peripheral blood cells taken for rheumatoid arthritis patients, which has been stimulated with anti-CD3 and anti-CD28. Rosnilimab is represented in blue, our competitor is in orange. The dose range expected in clinical studies is shaded in gray. On the upper left, both molecules show depletion of PD-1 high cells. However, our competitor reaches a plateau of effect around 1 nanomolar, whereas rosnilimab shows continued depletion. On the next 3 panels, we see similar findings, better inhibition of T cell proliferation, better reduction of CXCL13 levels, the cytokines secreted by Tfh and Tph cells and better inhibition of TNF, and inflammatory cytokine and known clinically validated driver of rheumatoid arthritis. The several of these assays, we see continued improvement throughout the clinical dose range. This consistently is not seen with the competitor molecule suggesting rosnilimab has the potential to drive deeper responses. There is significant need to improve the standard-of-care in RA. Synovial heterogeneity is a barrier to better outcomes. At Anaptys, we believe this can be uniquely addressed by the PD-1 agonist class through simultaneous targeting of multiple key pathogenic drivers. The PD-1 agonist cost is clinically validated in RA. Rosnilimab's differentiated profile has the potential to deliver best-in-class outcomes in its ongoing Phase IIb clinical trial. Now we will shift gears to address rosnilimab's potential in ulcerative colitis. Anaptys is excited to lead the field here, initiating a first-in-class Phase II trial in this disease. To help us understand the need for better treatment options in UC, I am delighted to introduce Dr. Sands, Professor and Chief of Gastroenterology at the Icahn School of Medicine at Mount Sinai.

Thank you so much, Cailin. It's a pleasure to be here with you and the group. And I'm pleased to be able to present to you information about ulcerative colitis, touching upon disease pathogenesis, the treatment landscape and the unmet need. Here are my disclosures, potential conflicts of interest, most importantly, I'm an Adviser to a AnaptysBio. What I'd like to do is, review the pathogenesis of ulcerative colitis and cover an understanding of the treatment landscape and the unmet need. Will also consider the role of PD-1 as a target mechanism of action in ulcerative colitis. Ulcerative colitis is a chronic inflammatory condition that inflames the mucosa of the large bowel generally from the rectum and proceeding approximately. You can see in the pictures on the lower left-hand side, various degrees of information as is categorized by the Mayo endoscopic score, part of the total Mayo Clinic Score, which also includes stool frequency and rectal bleeding score as well as a physician global assessment score, which in some comprises the total Mayo Clinic Score. Stool frequency and rectal bleeding are the cardinal symptoms of ulcerative colitis. The burden of disease is very significant for these patients. First of all, there are at least 1.5 million people in the United States who suffer from ulcerative colitis. On the left-hand side, you can see that a large percentage of patients more than half feel that their condition is really controlling their lives. And this is more to a greater degree than what we see in asthma, migraine and rheumatoid arthritis, other chronic conditions. You can also see that there is a very heavy psychological impact of ulcerative colitis. Many patients worry about the long-term effects of the disease. They have fillings of embarrassment. They may find that their life is more stressful and some of them also experience depression. It also affects the people around them, their families, because the disease has a typical onset at a median age of 30 years old, and therefore, half the patients are diagnosed before that time and half after that time through the full lifespan. But you can see that these are patients very much in the prime of their lives. So these impact is enormous. We have a growing understanding of the basis of this chronic inflammatory condition that we call ulcerative colitis, which falls under the broader terminology of inflammatory bowel disease. And you can see that there's a growing understanding that pathogenesis is driven by an abnormal dysregulated immune response, probably to the normal bacterial flora, although, there is a clear understanding that there's a dysbiosis in patients with inflammatory bowel disease. The genetically predisposed host may have a trigger that then leads to chronic inflammation. And what we end up in Phase III of this is a chronic phase without resolution, which centers on T effector cells. The T effector cells are really central to the pathogenesis. They are reacting downstream of the microbiome effects, and this goes on and on in an unremitting fashion to lead to bowel damage and all the symptoms that we remarked upon before. And finally, you can get tissue destruction, fibrosis, scarring and other complications of the disease. So many of the treatments that we have at hand do address this chronic phase of inflammation and, in fact, do target T cells and other inflammatory and immune mediating cells. Fortunately, we have seen a rise in an understanding of the pathogenesis of IBD, and that has led to the emergence of novel biologic therapies, as well as small molecule advanced therapies. You can see that over the last few decades, we've had the emergence of anti-TNFs, which really are the backbone of advanced therapy for the majority of patients with moderate to severe ulcerative colitis. Then we had anti-alpha-4/beta-7 in the form of vedolizumab. We had anti-P40 antibody blocking IL-12 and IL-23 in the form of ustekinumab. And eventually, we have had JAK inhibitors such as tofacitinib and filgotinib and upadacitinib, and more recently, we've had the approval of ozanimod in S1P1 receptor modulator another oral therapy for the treatment of ulcerative colitis. Unfortunately, none of these medications treat the majority of patients and make them submit the disease into remission for long-term. And we see this, in particular, with the backbone therapy, which are the anti-TNFs, they're really the cornerstone of IBD treatments, including ulcerative colitis, but first of all, not all patients respond to induction therapy and many other patients who lose response over time. I'm showing you data here on the left from Crohn's disease, where it's estimated that up to 1/3 of patients don't respond to induction therapy and another quarter to as much as half of the patients lose response within the first year of treatment with something like 15% annual loss of response in subsequent years. The data are more limited in ulcerative colitis, however, in Phase III trials, primary non-response rates with infliximab were somewhere in the range of 30% to 40% and more than half of initial responders lose response to treatment in the first year. So the problem is every bit the same in ulcerative colitis. So despite all of these advances in the treatment of ulcerative colitis, there still is a major unmet need for other kinds of therapies, other mechanisms of actions and better response and remission rates preferably remission. We've learned over time that targeting a single mechanism of action may not be sufficient to break through this therapeutic ceiling. And we had a very intriguing result from the VEGA study, which combined an anti-TNF golimumab already approved for the treatment of ulcerative colitis with an anti IL-23, guselkumab, which is being investigated for ulcerative colitis and has been shown to have efficacy as a monotherapy though not yet approved. And compared these monotherapies to combination therapy of both golimumab and guselkumab. And you can see here that there was a near doubling of the clinical remission rate at week 12 without any change in the safety profile. This suggests that targeting multiple mechanisms, more than one therapeutic target at the same time, may provide an opportunity to break through the efficacy ceiling that we're seeing with monotherapies and moderate to severe UC. Interesting work published more than 8 years ago, examined the role of T cells in association with the course of a variety of immune-mediated diseases, including IBD, by applying weighted gene co-expression network analysis to the transcriptome of CD4 and CD8 T cells from prospective cohorts. The investigators identified a module corresponding to T cell co-stimulation that was strongly associated with flare-up disease. What the investigators observed was that the CD8 T cells expressing PD-1 demonstrated an exhausted phenotype characterized by progressive loss of effector function and persistence expression of co-inhibitory receptors such as PD-1. And as you can see in the bottom figure for the IBD cohort, patients with a T cell gene expression characteristic of exhausted T cells depicted in blue have a significantly longer flare-free survival. The conclusion is that T cell exhaustion, which is a result of PD-1 agonism should have a beneficial effect in treating autoimmune inflammatory diseases such as inflammatory bowel disease or specifically ulcerative colitis. Additionally, we now know that novel subsets of T cells, in particular, T follicular helper cells and T peripheral helper cells are expanded in ulcerative colitis and may direct the B cell response, which is known to be deleterious. These cells -- these T follicular helper like cells identified in the colon of patients with ulcerative colitis are novel population, they're characterized by expression of a variety of markers, including PD-1, CXC chemokine receptor 5, inducible costimulatory molecule or ICOS, and B cell lymphoma 6 or BCL-6, and they all produce IL-21. Much of this is in common between T follicular helper and T peripheral helper cells. And as you can see from the evidence on the right, these cells are significantly increased in active ulcerative colitis patients compared to those in stable remission with UC and healthy controls, UC higher Mayo Clinic Scores, higher inflammatory biomarkers. And you also see these cells in the germinal centers increased in UC colons compared with controls. And the level of T follicular helper cells are positively correlated with the circulating new memory B cells, plasma blasts, serum IgG, IL-4 and IL-21, all markers of immune activation. And so, given that PD-1 is expressed on these cells, it seems in particular that PD-1 would be a good target. So in summary, ulcerative colitis is a high impact disease. There's a high personal and economic impact and rising rates globally. We see significant therapeutic limitations with the drugs that we have at hand, both in terms of safety of agents, such as the anti-TNFs and JAK inhibitors and limited efficacy in achieving and maintaining remission. We believe that targeting multiple mechanisms may provide an opportunity to break through the ceiling of efficacy that we're observing with all of our monotherapies. And we've also seen that the PD-1 pathway is implicated in immune-mediated disease, including ulcerative colitis. Therapy is impacting T effector cells have been proven efficacious and PD-1 positive T follicular helper and T peripheral helper cells expanded and you see may direct the B cell response. Therefore, PD-1 agonism has the potential as a novel mechanism of action for the treatment of ulcerative colitis with strong preclinical rationale. So I thank you for your attention.

Thank you, Dr. Sands. Our translational data give us confidence that PD-1 agonism and specifically rosnilimab can deliver differentiated outcomes in UC. Rosnilimab hits key mechanisms driving efficacy for currently approved agents in UC, which target T cells. Specifically, you can see the IL-23s. The TL1A and the JAKs that broadly hit cytokine signaling and related T cell activity. The anti-integrins prevent migration of T cells from the periphery into the tissue. And the S1Ps prevent the e-flux of T cells out of lymph fluids, thereby preventing migration into the tissue. Each of these biologies is addressed by rosnilimab through either depletion or agonism of the PD-1 high and PD-1 intermediate T vector cells in the lymph node, in the periphery and in the tissue. This will lead to a reduction in T cell migration, proliferation, inflammatory cytokines and cytotoxic T cell activity that's disrupting the colonic barrier function and contributing to inflammation in UC patients. Additionally, through Tph cell depletion, rosnilimab targets B cell pathology that leads to auto antibody generation, including anti-microbial IgG antibodies that are unique in ulcerative colitis. Much like autoantibodies RA that drive pathology in the joints, antibodies against microbes and UC likely contribute to persistent inflammation in the colon. We shared the immunohistochemistry showing the enrichment of T cells, about 40% of T cells in the lamina propria are PD-1 positive. Flow cytometry from colonic biopsies as shown in the lower left, demonstrates an enrichment of PD-1 expressing T cells. These T cells can be analyzed to look at their gene signature and the status of PD-1 signaling. For example, the upregulation of T cell activity induced by nivolumab. Similar to what was observed in RA synovium on the right, we show T cells in the colon demonstrated an insufficiently agonized PD-1 signature. With appropriate PD-1 agonism, we would expect this signature to be reversed and brought back to balance. These data suggest that very similar to what we see in RA. The T cells are not being turned off in the inflamed colon of UC patients, and they remain in an activated state. In the colon, there's an enrichment of Tph cells, especially in the inflamed colon, as seen in the left graph. Most importantly, in the middle graph, PD-1 high Tph cells are elevated in the peripheral circulation of active UC patients and patients who are treated and achieved remission have a dramatic reduction of circulating Tph cells. In the figure on the right, shown at the individual patient level, patients effectively treated with 5-ASA that achieved stable remission also have a dramatic reduction in circulating PD-1 high Tph cells. These data suggest that PD-1 high Tph cells are drivers of clinical disease activity and the reduction may lead to remission. There are also a number of animal studies where the role of PD-1 agonism is assessed in mouse models of colitis. In the figure on the left, human PD-1 expressing CD4 T cells were transferred into a mouse to induce colitis. Animals were prophylactically dosed with a PD-1 agonist HM226, and it prevented the induction of colitis. We ran a similar study using rosnilimab. We also transferred human PD-1 expressing CD4 T cells into the mice, but differently from what was done in the prophylactic study and representing a higher bar to achieving efficacy. We waited for disease onset. Then we dosed rosnilimab therapeutically to induce and maintain remission from colitis, that has already began to show symptoms. These studies demonstrate that PD-1 agonist like rosnilimab can be used to treat ulcerative colitis. Lastly, PBMCs from ulcerative colitis patients were activated with anti-CD3 and anti-CD28 similar to studies in RA. Across all these graphs, you can see a clear impact of rosnilimab treatments at concentrations that are clinically relevant shaded in gray. On the upper left, rosnilimab demonstrates potent depletion of PD-1 high T cells through the clinical window. On the next 3 panels, we can see similar findings, inhibition of T cell proliferation, reduction of CXCL13 and IL-21 levels, and inhibition of interferon gamma and inflammatory cytokine in ulcerative colitis. These endpoints suggest that we'll have bone defects on pathogenic PD-1 expressing T cells in the treatment of ulcerative colitis. In summary, reducing elevated PD-1 high Tph cells in both the lamina propria and periphery correlates with disease remission. Translational work in multiple animal studies shows the ability of PD-1 agonist to treat colitis. And rosnilimab's potent immunologic effects are supported by preclinical data from UC patient samples. Now Paul Lizzul, our Chief Medical Officer, will describe our clinical results to date and our Phase II trials in RA and UC.

Thanks, Martin. Now I will walk us through a summary of our prior Phase I and II data and then discuss our plans for ongoing clinical development in Phase II in both RA and UC. Beginning with our previously shared Phase I data, we observed a favorable pharmacokinetic profile with an estimated 2 week half-life for subcutaneous and intravenous routes of administration. In addition, full PD-1 receptor occupancy was observed rapidly during the first week, following single subcutaneous rosnilimab doses and was maintained for greater than 30 days in a dose-dependent manner. These data support the potential for at least monthly subcutaneous dosing of rosnilimab for future patient trials. Overall, the incidence of ADA was also generally low and did not affect either PK or safety. In terms of safety and adverse events, rosnilimab was well tolerated. AEs were balanced relative to placebo, mostly mild to moderate in severity and with no AEs leading to treatment or study discontinuation, and no treatment-related SAEs. To put this into further perspective, Lilly also reported in their 100-plus patient Phase IIa RA study, a similarly clean safety profile that was balanced relative to placebo with no related SAEs, and that's despite dosing quite high at 700 milligrams IV monthly for 6 months. Moreover, there was also no carcinogenic risk and no infection signal seen to date for the competitor PD-1 agonist and that is also consistent with what has been seen with rosnilimab to date as well. Additionally, abatacept with an MOA, which broadly [ T cells ] rather than the specific PD-1 positive subset only has been used in diseases such as RA for decades and has not shown clinically relevant increases in overall carcinogenic risk. In summary, rosnilimab and the PD-1 agonist class overall have been tested in many hundreds of people and have been well tolerated with no dose limiting toxicity observed to date. Focusing further on safety in our 45 patient Phase III study in alopecia areata with the subcutaneous monthly dose of 400 milligrams for 6 months, we observed no unexpected or concerning signals. As you can see from the table, AEs were balanced between rosnilimab and placebo, and there were no treatment-related serious or severe AEs and no increased incidence of infections. So consistent with the Phase I study results, in alopecia areata patients, rosnilimab was also well tolerated and the overall safety profile looks to be unremarkable. Now let's review the impact on pharmacodynamics in the periphery, comparing our Phase I results in healthy volunteers shown in the upper left graph, with our Phase II results in alopecia areata patients shown in the lower left graph. Overall, the T cell composition moved to a less activated state. Importantly, in both studies, we saw a rapid greater than 50% reduction in PD-1 positive T cells shown in the orange lines and a 90% reduction of PD-1 high T cells shown in the red lines. This consistent, potent and sustained reduction of PD-1 positive T cells lasted for greater than 30 days post rosnilimab treatment in each study, and as long as 3 months in the alopecia areata treated patients. While beginning to increase, the number of PD-1 high T cells remain meaningfully below baseline levels, demonstrating a durable pharmacodynamic effect. This is encouraging in the context of RA and UC, which are systemic disorders with multi-fold increase in PD-1 positive T cells. However, alopecia areata is not a systemic disease, and there is no significant increase in peripheral PD-1 positive T cells relative to healthy controls. As we previously disclosed, we did not see patients achieve the desired efficacy endpoint on SALT score less than 20 in this study. In scalp biopsy samples, only about 10% to 15% of T cells were PD-1 positive, scattered in the layers of the skin, and we saw target engagement confirming rosnilimab tissue pharmacology. However, at the hair follicle itself, which is the site of pathology, PD-1 positive cells were essentially undetectable in these patients. They simply were not there. For this reason, treatment of alopecia areata with the PD-1 agonist is not the right approach. Encouragingly, between the depletion we observed in the periphery and the target engagement in the scalp, we achieved proof-of-mechanism. And in contrast to alopecia, greater than 80% of T cells in the synovium in RA patients and greater than 40% of T cells in the lamina propria and UC patients are PD-1 positive T cells. These insights support our rationale and confidence in our RA and UC Phase II trials. Now let's review our Phase IIb global trial for moderate to severe RA patients. The dose ranging study includes 3 active rosnilimab dosage arms versus placebo, equally randomized in approximately 420 total patients at a 130 participating sites in North America, South America and Europe. We will be enrolling patients and stratifying results based on previous treatment experience. This will include biologic-naive patients who have previously been treated with conventional DMARDs, such as methotrexate and patients who are experienced or been previously treated with 2 or less advanced biologic or targeted synthetic DMARDs. We're targeting enrolling approximately 50% of these patients. Patients will receive study drug dosed either every other week or monthly through week 12 with the primary endpoint assessment at week 12, measuring the mean change from baseline in the DAS28-CRP, as well as other common secondary endpoints, including ACR20/50/70 and the CDAI response. At week 14, rosnilimab-treated patients who achieved low disease activity defined as a CDAI score of less than or equal to 10 will then be dosed for an additional 16 weeks in an all active treatment period. Overall, we will assess rosnilimab in patients for up to 6 months on active drug. After the active dosing completes, patients will be followed for an additional 3 months to understand the longer-term safety as well as the off-drug efficacy profile. We initiated this trial in August and are guiding to top line data based on the primary end point by mid-2025. Next, for UC. The dose-ranging global Phase II trial in moderate to severe patients includes 2 active arms versus placebo, equally randomized in approximately 130 patients with more than 100 sites participating in North America and Europe. We'll be enrolling patients and stratifying results based on previous treatment experience. This will include biologic naive patients who have previously been treated with conventional therapies, such as 5-ASA and patients who are biologic experienced or have been previously treated with 2 or less advanced therapies. We are targeting enrolling approximately 50% of these patients. Patients will receive study drug through week 12 with the primary endpoint assessment at week 12, measuring the mean change from baseline in the modified Mayo Score, as well as other secondary endpoints, including clinical response, clinical remission, and histological improvement. rosnilimab-treated patients and placebo patients who achieved clinical response will continue on their original assigned treatment and be followed for an additional 12 weeks, while placebo subjects who are non-responders will be crossed over to the high-dose rosnilimab treatment arm in an all-active treatment period. Overall, we'll assess rosnilimab in patients for up to 6 months on active drug. Similar to the RA study, after the active dosing completes, patients will be followed for an additional 3 months to understand the longer-term safety as well as the off-drug efficacy profile. We'll initiate this trial by the end of the year, and we're guiding to top line data based on the primary end point by the first half of 2026. We have also invested significantly in our translational medicine capabilities this past year. In addition to robust safety and clinical efficacy assessments, both Phase II studies will also include supportive translational analyses. We have in-depth plans to study blood, synovium, and colon biomarkers with the goals of understanding the impact of rosnilimab on both systemic and tissue pharmacodynamic markers, developing predictive markers for precision medicine approaches, and immune profiling to explore rosnilimab's a broader potential to restore immune balance and the overall impact of agonism. We're excited to use these data to deliver breakthrough clinical results with rosnilimab in these heterogeneous diseases and apply these learnings to future indications and study design. In summary, we're building our programs on a solid foundation of safety data and translational insights, both from our own studies and the PD-1 agonist class in general. We look forward to sharing these top line data with you. And now I'll turn the call back over to Dan for some closing remarks.

Thank you, Paul. We'll finish up here by reviewing why we are so excited to have the opportunity to develop this new class of biologics in both RA and UC. Beginning with RA, as Dr. Graf noted, real-world data show less than 60% of patients achieve remission. 0.5 million of them in the U.S. have progressed beyond TNF therapy. Today, this post-TNF market is greater than $10 billion in the U.S. alone, and surprising to some, is highly fragmented, with no clear choice for these biologic experienced patients. In fact, most patients end up cycling through various classes of therapies, given the lack of efficacy. In addition, there has not been a new therapeutic class approved in over a decade, and our market research suggests, given the significant need, there is a desire for a new, safe, and differentiated therapeutic class that addresses improvements to clinically and commercially meaningful endpoints, such as ACR50 and ACR70. On the left of this slide, these patients have progressed on methotrexate and they only achieve response rates of around 30% ACR50 and 10% ACR70 on TNFs, the standard of care. And on the right, as patients cycle beyond these TNFs, these low response rates worsen across all classes of therapy. Initial Phase IIa data from Lilly's PD-1 agonist, represented by the horizontal blue bars, shows highly-differentiated data from all other classes of drugs on both the ACR50 and ACR70. Even more exciting, as Cailin showed earlier, this PD-1 agonist class seemed to have consistent responses in both biologic naive and biologic experienced patients, and for those patients who responded by month three, they sustained their response through six months of dosing. These data support there is an opportunity with rosnilimab to break through the historically low efficacy ceiling, which is incredibly exciting and achievable. UC is another disease that, regardless of the breadth of treatment options available, unfortunately lacks a highly effective option to both induce and maintain clinical remission. The UC market, excluding the TNFs, is rapidly growing, with U.S. sales projected to be $6.5 billion by 2028. Similar to RA, it is also a highly-fragmented market. Severe patients have no clear choice after progressing on TNFs and moderate patients will often settle for lower efficacy in favor of safety. Across this treatment landscape, clinical remission is only in the 20s to low 30%. And if they were lucky enough to achieve remission in the induction phase, 1/3 to 1/2 of patients relapse within a year. Refractory patients may consider JAKs, given they are on the higher end of these efficacy ranges, but this comes with a safety tradeoff. The moderate biologic-naive patients utilize treatment options with a more tolerable profile such as the alpha4beta7s but this comes with less efficacy. We see a significant opportunity to differentiate with a first-in-class approach in UC, one that is tolerable, safe, drives deeper responses through the induction phase, and is suitable for a broad patient population. There is also potential to restore immune balance leading to sustained outcomes in the maintenance phase. Anaptys is a leader in developing checkpoint agonists. We have great conviction in rosnilimab, a best-in-class PD-1 agonist in Phase II development for RA and UC. We're grateful to Dr. Graf and Dr. Sands for their expertise, our Anaptys team, and the patients and families we serve. Thanks for listening. Cailin, Martin, Paul, and I will now hand the call over to the operator for our first question.

[Operator Instructions] Our next question comes from the line of Yatin Suneja of Guggenheim.

Thank you for putting this good presentation and walking us through the mechanism. Very helpful. I have maybe 2 questions. First is on the preclinical model that you use for UC. Can you just expand on the model that you used on Slide 54? How predictable is that model? And did you look at other models like DSS model, adoptive transfer model? Would love to hear the findings there. And then in terms of the -- again, sticking with UC, do you expect this mechanism to be equally effective in naive versus biological experience? Or do you think there is more rational in naive, maybe less in biologic, or one way or the other. Just would love your thoughts on these 2 points.

We used the CD4 transfer model that was identical to the model identified by Suzuki et al.'s paper, which was the paper that described the identification of the PD-1 agonist binding to epitope 7. In that model, we transferred human PD-1 expressing T cells into the mice. Those T cells [ expand and they drive ] the colitis in those animals. And they could use that antibody to prevent the onset of disease by dosing prophylactically. And we could use rosnilimab in that same model in a therapeutic approach to prevent and induce remission in those animals. We do believe it could be predictive of what could happen in the UC patients where we would be able to treat existing disease and reduce ongoing inflammation.

Paul, you want to start...

Yes, sure. On the second one, rephrasing the question, I think it was around efficacy in naive versus experienced patients. And I would say, given this broad mechanism of action of PD-1 targeting of the cells, the anticipation would be we would anticipate to see efficacy in both naive patients as well as those who have undergone treatment with other potential therapies such as anti-TNFs. And we'll be looking at both of those populations in the study as well to confirm that.

Our next question comes from the line of Anupam Rama of JPM.

I had like broader strategic question, if that's okay. So you guys outlined the mechanistic rationale for rosni here in ulcerative colitis and certainly the unmet need in the indication as highlighted by the KOL on the line. I'm just wondering when you put up a whiteboard of indication options, you chose something larger, more competitive, something that may require a pretty large-scale Phase III trial, maybe a partner, versus something smaller, less competitive, with a significant unmet need, something that you could maybe take on yourself as a small biotech. Walk us through like what ultimately led to the second indication decisions.

This is Dan. So look, that's a good question. And there's no shortage of choice for the breadth of diseases that we had the opportunity to treat here. We think there's a lot of applicable areas. What's compelling to us around colitis, again, to your point, if you step back, we've initiated 3 Phase II trials this year, about to initiate a third in UC this year across 3 therapeutic areas and 2 agonists. And a consistency here across all of them, they are systemic, heterogeneous inflammatory diseases that have benchmarks that we think are pretty low in the standard-of-care. We're talking across all these 20%, 30% response rates where there's satisfied patient populations. And to us, it really just exemplifies how much opportunity there is when you're sitting here taking a top-down approach with immune cell modulators that can broadly impact disease pathology. Part of what we also outlined here, beyond our own mechanism, is highlighting proven proof of concepts from other therapies that are out there that really only impact a small portion of what we expect to do with rosnilimab or our BTLA program in AD. So the consistency of that -- I push back on you a bit here. We do think we can execute robust Phase III trials and diseases like atopic dermatitis and here in UC. I think there's precedence for that. We think about the commercial opportunity here, you don't need to get to a tremendous amount of docs to commercialize these yourselves. And these are still emerging growth areas. One of the highlights here for UC, for us, is it's $6.5 billion market projected in 4 to 5 years, and that's growing rapidly into that. AD is similar, with new classes emerging right now as opposed to [ instill ]. And even with RA, when you classify it that way, the significant difference in the 1 disease where there is proof of concept with this mechanism of action, PD-1, with Lilly's data, it's such a significant difference relative to the other biologics that are out there where I think what you're really asking is can we stand up and enroll these trials. And I think the answer is yes. And hopefully we'll show that in just the Phase II's over the next 1 to 2 years.

Our next question comes from the line of Eliana Merle of UBS.

Just a question on the dose levels in the studies. Specifically, how are you thinking about the dose level in UC relative to RA and any potential differences in the doses that you expect would be needed in UC? Just from the slides, it looks like you're studying 3 dose levels in RA and 2 in UC. Maybe can you just walk us through your thinking there? And I guess if the dose levels are the same or higher or lower between either of the studies?

Yes. We haven't specifically given the exact dosage levels for competitive reasons, but we are looking at a broad dose range and obviously taking into account information we have from earlier studies, PK and the alopecia study as well. So it'll provide us with an opportunity to again look at a broad dose range in both indications and then based on those results, that'll set us up for an opportunity to progress into further clinical development.

I'll just add to that, just to repeat it from earlier in the presentation, we're looking at every other week but also monthly dosing in all of these trials. We think that's feasible based on what we see and what Paul just described across the breadth of active cohorts in both trials.