Thank you for standing by and welcome to the ANB033 CD122 Antagonist Virtual Investor Event. At this time, all participants are in listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during this session, you'll need to press star one-one on your telephone. If your question has been answered and you'd like to remove yourself from the queue, simply press star one-one again. We ask that you please limit yourself to one question each. You may get back in the queue as time allows. As a reminder, today's program is being recorded. And now I'd like to introduce your host for today's program, Daniel Faga, President, Chief Executive Officer, and Director of AnaptysBio. Please go ahead. Good afternoon and thanks for joining. We're excited today to focus on ANB033, a potential best-in-class CD122 antagonist that represents its own pipeline and product for the treatment of autoimmune and inflammatory diseases. This presentation contains forward-looking statements. As we recently announced, in 2026, we intend to separate our biopharma operations from our substantial royalty assets. This separation is designed to maximize value by creating two independent, publicly traded companies, each with different business objectives and opportunities. Much like AnaptysBio does today, the company we are generically referring to as BiopharmaCo will continue to develop and potentially commercialize our three clinical stage programs. Each of our assets targets pathogenic cells that are significantly elevated in autoimmune diseases but are only present in lower trace amounts in healthy tissue. Our antibodies are designed to potently eliminate or modulate these specific disease-driving cells. ANB033 was discovered by our team at AnaptysBio and is anticipated to be an important part of BiopharmaCo's asset base. We have initiated a phase 1B trial in celiac disease and expect to initiate a trial in a second indication in 2026. We believe targeting CD122 has a strong biologic rationale. For background, IL-15 and IL-2 signaling pathways are essential regulators of immune cell activation and function. High levels of these cytokines drive proliferation and survival of immune cells, resulting in disease pathology. These specific immune cells express our target of interest, CD122, which is the shared receptor subunit through which IL-15 and IL-2 signal. We believe this approach to inhibiting signaling of both cytokines will deliver a greater therapeutic impact, positioning a CD122 antagonist as an attractive target for drug development. ANB033 was designed with an optimized binding epitope and affinity to CD122, which potently inhibits both IL-15 and IL-2 signaling. We believe these differences contribute to ANB033's best-in-class profile. Martin will review preclinical and comparative pharmacology data to support this view later in the presentation. Targeting CD122 has broad therapeutic potential, including in GI, dermatology, and other therapeutic areas. The IL-15 pathway is being explored in clinical development by multiple global pharmaceutical companies. Novartis, through its 2024 acquisition of Clipso, generated clinical proof of concept in both celiac disease and eosinophilic esophagitis (EOE). Forte recently reported positive phase 1B data with its CD122 antagonist in celiac disease. Within the derm space, there are ongoing trials in vitiligo by Teva, as well as by Incyte, who is developing a first-generation CD122 antagonist. ANB033's mechanism targets multiple pathogenic drivers of inflammation in celiac. Celiac patients have an immune response to gluten, which rapidly induces IL-2. Inhibiting this signal reduces CD4+ memory T cell inflammatory activity. In parallel, inhibiting both IL-15 and IL-2 on intraepithelial lymphocytes should contribute to restoring barrier integrity. There is compelling justification for developing a therapy for celiac, which has a high disease burden. The only preventative measure is a gluten-free diet, which is highly restrictive and poorly tolerated in many patients. More than 50% of patients suffer from anemia or fatigue. There are approximately 2 million celiac patients in the U.S., and the diagnosed nonresponsive celiac population is projected to exceed 250,000 by the early 2030s. However, what would otherwise be a $4- $5 billion U.S. market does not have any approved therapies. As I highlighted, there are many additional diseases where ANB033 may be an effective treatment option. We're internally exploring a few of them and are committed to initiating an additional proof of concept study in 2026. One ongoing assessment is in EOE, another autoimmune disease treated by many of the same gastroenterologists as in celiac. Unmet need here is also high, and treatment options for this disease are limited. Today, we'll share some initial perspectives on the biologic rationale and preclinical data we've generated in EOE. During our call, Dr. Martin Dahl, AnaptysBio's Senior Vice President of Research, will dive into the biologic rationale for targeting CD122 and preclinical data with ANB033 in celiac and EOE. Discussing ANB033 phase 1A clinical results will be our Vice President of Clinical Development and lead physician in our celiac trial, Dr. John Kwan. Phase 1B trial design for celiac will be our Chief Medical Officer, Dr. Paul Lizzul. We're also excited to be joined by Dr. Joe Murray, Professor at the Mayo Clinic College of Medicine in Rochester, Minnesota, who will share his clinical expertise in celiac disease. Now, I'll turn it over to Martin. Thanks, Dan. CD122, also referred to as the IL-2 receptor beta subunit, is part of the shared receptor for IL-15 and IL-2. These pathways are integral to the regulation and activation of immune cells, particularly subsets of cytotoxic CD8+ T cells, CD4+ TH1 and TH2 cells, and NK cells. Dysregulated signaling by these cytokines contributes to the survival or persistence of these cell types, as well as their proliferation and inflammatory responses, which can result in autoimmune and inflammatory diseases, including celiac. Intraepithelial lymphocytes, or IELs, consist primarily of cytotoxic CD8+ T cells and a minority of NK cells. These are highly pathogenic cells expressing CD122 that are prevalent in the gut and celiac. ILC2s are innate immune cells that secrete large amounts of type II cytokines, primarily IL-5 and IL-13. ANB033 binds to an optimized epitope with high affinity that leads to a differentiated inhibition of both IL-15 and IL-2 signaling. The binding epitope of ANB033 was mapped, and as you can see on the left, sits squarely within the IL-15 and IL-2 binding footprints. In the middle of the slide, we used an in vitro cell-based STAT5 reporter assay to show ANB033's potent effect of inhibiting the signaling of IL-15 and IL-2, particularly within the range we expect to achieve in the tissue, as shown in the gray boxes, giving us flexibility to treat various diseases. On the right, we show ANB033 potently inhibits the proliferation of primary immune cells from human PBMCs, NK, cytotoxic CD8+ T, and memory CD4+ T cells, which express the high affinity IL-2 receptor. Notably, ANB033 increases the proliferation of Tregs. This effect is different than on memory CD4+ T cells since Tregs express very high levels of CD25, which binds enough IL-2 to allow them to maintain their proliferation, survival, and express FOXP3. An aggressive GVHD model in human IL-15 expressing transgenic mice that support the engraftment of human T and NK cells shows the in vivo activity of ANB033. This model progressed very quickly as isotype-control treated animals died within a median survival of only 14 days. ANB033 in blue demonstrated a significant improvement in survival, particularly after the last dose, compared to other treatments. Correlated on the right, ANB033 treated mice lost less body weight compared to isotype control or other treatments. On day 17, where there was ongoing inflammation, we measured gene expression from purified human cells. ANB033 was the only treatment that significantly reduced the expression of numerous granzyme-family genes, which mediate the killing properties of T and NK cells. We also evaluated ANB033 in a 13-week cynomolgus monkey GLP-Tox study with weekly dosing and an eight-week recovery period. Shown here are the 10 and 100 mg/kg dosed cohorts. On the top left, ANB033 induced a rapid reduction of CD122-positive cytotoxic CD8+ T cells. In the overall CD8+ T cells on the bottom left, there was a more modest impact. This reduction lasted the duration of the dosing period and began to return toward baseline during the recovery period in the 10 mg/kg dose, which is most similar to the dose range anticipated for human trials. On the top right, we also observed the expected reduction of CD122-positive NK cells. For awareness, CD122 is highly expressed by virtually all NK cells in the cynomolgus. This is specifically not the case in humans. We also observed a return towards baseline in the recovery period for NK cells in the 10 mg/kg dosed animals. Throughout the tox study, ANB033 was safe and well tolerated. There were no drug-related toxicities and specifically no viral infections. The NOAEL provides a tenfold safety margin over our dosing used in the celiac phase 1B trial. Now, we'll look at single-cell RNA sequencing data from human celiac intestinal biopsies. The graph on the left shows in blue the dense expression of CD122 by infiltrating CD8+ and CD4+ T cells and NK cells in the immune compartment of human celiac tissue. Importantly, CD122-positive cells are increased in celiac tissue by 50% to 150% compared to healthy. Depicted in red is the extensive expression of IL-15 by structural cells such as epithelial cells. On the right, you can see similar dense expression of interferon gamma and granzyme B. These data highlight the critical role of CD122-positive cells and IL-15 expression in the pathogenesis of celiac. This illustration shows celiac biology with gluten captured and presented by APCs to CD4+ T cells. This causes a cascade of immune activation. The purple box highlights how ANB033's blocking of IL-15 signaling prevents the inflammatory effects of IL-15 on IELs, reducing the downstream mediators of tissue damage by inhibiting the accumulation and killing activity of CD122-positive IELs. Importantly, ANB033 will also impact this bigger area, which is shown in the green box, modulating specific upstream immune pathways in response to gluten in individuals with celiac. This stops the disease at its source by reducing CD4+ T cell-derived interferon gamma and IL-2 signaling that would otherwise drive and amplify mucosal damage and by reducing downstream B cell-mediated antibody responses, including anti-gliadin and anti-tissue transglutaminase antibody production, which are real-world clinical measures for celiac. Apart from the impact on inflammation, these cytokines are correlated with the GI and flu-like symptoms associated with gluten ingestion. ANB033's dual inhibition of IL-15 and IL-2 signaling makes it an ideal therapeutic candidate for broadly addressing the underlying inflammatory mechanism driving mucosal damage in celiac. Many global pharmaceutical companies have or had celiac programs in development. However, none of these mechanisms target both IELs and CD4+ T cells. There are a number of active programs specifically targeting only the IL-15 cytokine, targeting the downstream mediators of celiac in the purple box, which have been shown to affect IEL survival. However, most other drugs are non-cell targeting mechanisms that attempt to impact gluten processing or presentation, as depicted in the red and orange boxes. Dr. Murray will speak further about other mechanisms that are being considered for celiac treatment. We believe the CD122 antagonist targeting both the key upstream pathogenic drivers and the downstream mediators of celiac will deliver meaningful therapeutic efficacy. In a mouse model of celiac that's been well characterized in literature, we tested an ANB033 surrogate antibody that binds to mouse CD122 on a similar epitope and with a similar high affinity to ANB033 in humans. Shown here are H and E stains from the intestines of each treatment group, including no gluten, sham, and normal histology, and then isotype control and ANB033 each challenged with gluten. The stains clearly show the mucosal damage caused by gluten and prevention of the damage in the mice treated with ANB033. It's comparable to the no gluten sham and strikingly different from the injury observed in the isotype plus gluten challenge. From the same study, you can see how we measured these findings by assessing villus height and crypt depth using the VH:CD ratio, an established endpoint in celiac. In the figure on the left, in healthy tissue, villus height is high relative to crypt depth, which is low. In contrast, in celiac data or in celiac tissue, we observed the destruction of villus with reduced height and extended crypt depth. On the right, the results from our celiac mouse model demonstrate that ANB033 significantly prevents reduction of the VH:CD ratio as compared to isotype control. This improvement highlights the potential of ANB033 to prevent tissue damage and the possibility to restore normal intestinal architecture in celiac patients. To demonstrate the cellular impact, we assessed the epithelial layer and the lamina propria of the small intestine using flow cytometry. On the left, in response to gluten, ANB033 prevents an increase in CD8 IELs and specifically prevents an increase in the subset of CD8 granzyme B expressing IELs. On the right, ANB033 similarly prevents the increase of CD4 interferon gamma-positive T cells compared to isotype control treated mice. Overall, ANB033, in reducing pathogenic immune cells in both upstream and downstream pathways, mitigated inflammation and tissue damage in celiac. Separately, we stimulated celiac patient-derived PBMCs with both IL-15 and IL-2 to assess the potency of ANB033 on inhibition of proliferation. ANB033, shown in blue, demonstrates very significant inhibition of proliferation both on cytotoxic CD8 as well as CD4 TH1 and TH2 cells that even express the high affinity IL-2 receptor. This inhibition was observed in concentrations we expect to achieve in the tissue in diseased patients. As shown on the bottom, we also stimulated these celiac patient-derived PBMCs with anti-CD3 and anti-CD28 to activate all of the T cells. ANB033 also significantly reduced granzyme B secretion and reduced interferon gamma secretion. Now, Dan highlighted the broad potential utility of a CD122 antagonist across a wide range of diseases in GI, derm, and other therapeutic areas. We're actively assessing a few potential additional indications with the intent to advance one additional proof of concept trial in 2026. One disease we're assessing that may be another strong match for ANB033's MOA is eosinophilic esophagitis (EOE), a chronic immune-mediated disease characterized by inflammation and damage of the esophagus. Let's look again at single-cell RNA-seq data like we did in celiac. Here we can view the various immune cells and expression patterns of cytokines in EOE tissue biopsy samples. The graph on the left shows in blue the dense expression of CD122 by infiltrating cells in human eosinophilic esophagitis (EOE) tissue. Notably, there's a prominent population of cytotoxic CD8+ T and NK cells relative to the number of CD4+ T cells and ILC2s. Depicted in red is the extensive expression of IL-15. On the top right is the CD4+ and ILC2 pathway and the expression of IL-13 and IL-5, two hallmark cytokines of EOE. In the lower right is the CD8+ and NK cell pathway and the expression of interferon gamma and granzyme B. I want to point out that there are two pathways here, a CD4+ ILC2 and a CD8+ NK pathway. The importance of the CD8+ NK pathway has really only recently been appreciated. Many of the same CD122-expressing cell types that facilitate the inflammation in celiac are also present in EOE. EOE is partially driven by alarmin-activated dendritic cells, CD4+ TH2 T cells, and ILC2s with prominent expression of TH2 cytokines such as IL-5 and IL-13. This pathway is targeted by dupilumab, an approved therapy for EOE. We refer to this as the CD4+ and ILC2 pathway, shown in the green box. Notably, we will show you data that ANB033 directly targets and reduces the activity of both of these cell types, including ILC2s. However, a second inflammatory pathway, which we refer to as the CD8+ and NK cell pathway, is not directly targeted by dupilumab, as shown in the purple box, which consists of highly activated CD8+ T cells, NK cells, and prominent interferon gamma secretion and granzyme B. Targeting this pathway is likely to improve symptoms of EOE by reducing inflammation, particularly in patients who are nonresponsive to Dupilumab. Both of these pathways are upstream and work together to cause downstream fibrosis and tissue remodeling, as well as other non-driving inflammation, such as the observed hallmark eosinophil recruitment and mast cell activation. This slide highlights the limitations of existing or failed therapies. Dupilumab has proven efficacy but does not address the full spectrum of immune pathways involved in EOE. As a result, 20%- 30% of patients do not respond to treatment, and additional patients could respond more optimally, also given the fact that we could address the CD8+ and NK cell-driven inflammation. As shown in the purple boxes, Novartis's anti-IL-15 antibody showed both eosinophil remission and a preliminary signal of symptomatic improvement in a small phase 1B study, reinforcing the hypothesis that IL-15 is a key disease driver which would not be targeted by dupilumab. This is despite anti-IL-15 not impacting IL-2 signaling directly, which drives both the CD4 ILC2 and CD8 NK cell pathways, pathways that contribute to mucosal damage and that ANB033 would target. Because of this, the collective impact of targeting CD122 may be more effective than Dupilumab or anti-IL-15 alone. Recent data from failed trials have also shown that targeting mast cells and eosinophils directly does not improve patient-reported outcomes, confirming downstream biologies are not drivers of EOE. To get an optimal outcome, we hypothesize you'd have to target both upstream immune cell-mediated inflammation pathways, which ANB033 can address. To look at the effect of ANB033 on the CD4 and ILC2 pathway, on the top half of this slide, we assess human PBMCs stimulated with anti-CD3 and anti-CD28 to activate all the TH2 T cells. On the bottom, we purified ILC2 from human whole blood and activated them with IL-2. In both assays, ANB033 potently inhibited secretion of both IL-5 and IL-13, demonstrating its ability to target the cells that represent the key MOA of Dupilumab. We also used the T cell activation assay to look at the effect of ANB033 on the CD8 and NK cell pathway. Human PBMCs stimulated with anti-CD3 and anti-CD28 activated all of the CD4 TH1 T cells and CD8 T cells. ANB033 again potently inhibited secretion of both interferon gamma and granzyme B, demonstrating its ability to target the cells that are also key drivers of inflammation in EOE. Finally, we studied the effect of ANB033 in a mouse model of aspergillus-induced eosinophilia. Eosinophilia is quantified from histology images, and as shown on the left, ANB033 reduced eosinophil infiltration in the esophagus as well as the lung. The histology images on the right show eosinophil infiltration in the lungs, and you can readily see the reduced eosinophil infiltration in the ANB033 treated group. These data are important because CD122 is not expressed on eosinophils. The reduced eosinophilia seen in this model is a result of ANB033 targeting the upstream immune cells responsible for the subsequent increase in eosinophils. These data validate the concept that by targeting CD122 on the upstream immune cells, we may effectively reduce eosinophilia in EOE. Now let's switch our focus to clinical data, and I'll turn it over to John. Thank you, Martin. Let's review the initial data from our phase 1A trial on healthy volunteers. All 10 cohorts, including four SAD intravenous, three SAD subcutaneous, and three MAD subcutaneous cohorts, have completed dosing. Each cohort had six healthy volunteers receiving drug and two receiving placebo, for a total of 80 overall participants treated with either ANB033 or placebo. For the higher SAD doses and all MAD doses, we are following participants for up to approximately seven months after last dose. To date, ANB033 has demonstrated an overall favorable safety profile and is well tolerated. There have been no SAEs, no severe adverse events, and no discontinuations. All adverse events were mild or moderate, with no signs of viral reactivations and with no unexpected lab abnormalities. Subcutaneous dosing of ANB033 has a two to three-week half-life and full receptor occupancy maintained for more than 30 days. A dose response was observed on relevant PD biomarkers, and we modeled the phase 1B dose in our celiac trial to achieve greater than IC90 on CD8+ T cell subsets in the target GI tissue. Importantly, no overall reductions were observed on regulatory T cell counts in the peripheral blood. In this slide, we conducted further flow analyses and assessed the impact of a single intravenous or subcutaneous dose of ANB033 on CD8+ T cells and NK cells. These doses represent maximal impact and PD of the dose we are taking forward in our phase 1B trial, demonstrating that ANB033 potently hits these pathogenic drivers of celiac disease. On the left, we see a potent effect with both these modes of administration, with a 70%- 75% reduction in CD122 expressing CD8+ T cells. However, this does not result in a meaningful reduction in overall CD8+ T cells. On the right, we effectively eliminate all CD122 expressing NK cells. In humans, not all NK cells express CD122. As expected, the overall NK cell count remains well above the levels needed to maintain immune competency. The impact of ANB033 on NK cells and its safety profile is consistent with what has been seen in other anti-IL-15s and anti-CD122 trials. As an example, Teva's anti-IL-15 demonstrated a similar reduction on overall NK cells. Note on the left, while our data only extend to day 85, subcutaneous dosing of ANB033 shows a trend toward recovery of NK cells within three months. While on the right, when you look at Teva's presumed dosing for later-stage trials in blue, Teva's recovery to 50% NK cells is seen up to one year after dosing. Regardless, their asset with recovery to baseline at 18 months was associated with no safety signals. Now, it is my great pleasure to introduce Dr. Joe Murray. He is a leading expert in celiac disease, co-founder and former President of the North American Society for the Study of Celiac Disease, and contributor to the 2013 guidelines and 2019 ADA practice update on celiac diagnosis and monitoring. We appreciate his participation today to discuss celiac drug development. John, thank you for that kind introduction. Celiac disease affects 1% of the population. It's a permanent intolerance to gluten that results in inflammation, destruction of the villi, crypt hyperplasia, and proliferation of intraepithelial lymphocytes, shown here on the right-hand side. The treatment of a gluten-free diet is not particularly acceptable to patients. Patients find it burdensome and have demonstrated an increasing dissatisfaction with it as a treatment. There are significant consequences of chronic active disease. GI symptoms, malnutrition, reduced quality of life, and consequences like osteoporosis are an increased risk of malignancy. Regardless of the gluten-free diet, perhaps as many as 50% of patients continue to suffer from things such as anemia and/or fatigue. Recent work has expanded our knowledge base of the cellular environment that occurs in the chronic inflammation of celiac disease. It's occurring in response to gluten. The gluten is incompletely broken down by human digestion. These peptides are taken up across the epithelium. They're deamidated in a way that makes them more antigenic by an enzyme called transglutaminase. Those peptides are presented in the context of a HLA molecule to CD4+ T cells that are specifically responsive to gluten in patients with celiac disease. This then drives a downstream inflammation. We know that even in treated patients, there's immune scarring that involves both epithelium stromal cells as well as these immune cells. We know in treated patients exposed to gluten, there is a rapid rise in IL-2 that happens within two hours of exposure. Stressed epithelial cells express the key cytokine of IL-15, characteristic but not unique to celiac disease injury. Key other roles of IL-15 include inhibition of regulatory T cells, expansion of T cells, especially the intraepithelial lymphocytes, as well as expansion and activation of NK cells. Some mechanisms that have been tried in celiac disease for potential treatments, many of which have reached clinical development, have focused on a whole series of these steps that we know are involved in pathogenesis. Attempts to genetically modify wheat have not been successful. Digesting wheat before it's turned into food or when it's in food, not also successful. Enzymes that can digest gluten within the gut have been tried in clinical trials, and we'll talk about one of those when we talk to clinical trial design. Other approaches like probiotics, binders are found either to be not tolerated or not effective. Regulators of permeability have been in clinical trials, and inhibitors of tissue transglutaminase have also been in clinical trials. We will come back to the last example here of a tolerogenic agent called Nexfax that we will discuss later in trial design. There is a rationale in targeting both CD8+ and CD4+ T cells to try to broadly impact celiac disease inflammation. Two key cytokines are IL-15 and IL-2. Both of these drive pathogenic immune cell expansion and inflammatory effects. IL-15 is an inflammatory cytokine expressed by stressed epithelial cells, including and especially in celiac disease. It supports T cell and NK cell homeostasis and expansion and binds intracellularly. It's expressed together with IL-15 with its IL-15 receptor on the cell surface in many cell types, including epithelial cells, stromal cells, and APCs. The expression in celiac disease occurs or is increased in the villi, in the crypts, and in the lamina propria. In addition, IL-2 stimulates CD4+ T effector memory cell activation and proliferation, as well as their production of interferon gamma, which we know is key to the injury that occurs in celiac disease and also drives IL-15 expression. The role of IL-2, which is produced by CD4+ T cells, has been well identified in the last five years in response to acute gluten exposure. A single exposure to gluten in a patient with healed celiac disease produces IL-2 and symptoms within two to four hours. IL-2 elevation is a key marker for the central role of these CD4+ T cells. This elevation is not observed in healthy controls, nor is it observed when there's a sham gluten or in patients with so-called non-celiac gluten sensitivity, and it occurs quickly. This also occurs in response to gluten peptide exposures. This is a result of that trial I mentioned about tolerance using an agent called Nexfax, made up of three peptides thought to be all derived from various parts of gluten, administered intradermally. In the run-in phase, patients were given an oral gluten challenge and showed a significant rise in IL-2, along with the occurrence in some of the symptoms. This did not occur after treatment with sham, but it did, unfortunately, for this agent, occur when they were re-challenged with gluten again. It was no different than the placebo. Again, a key marker for the response to gluten in patients with treated disease. IL-15 is a key driver of intraepithelial lymphocyte expansion. Mouse models overexpressing the IL-15 R-alpha receptor in epithelium result in an increase in intraepithelial lymphocyte expression. Mouse models for celiac disease that incorporate expression of IL-15 in villi or lamina propria or both, along with DQ8, the human HLA type, one of the human HLA types associated with celiac disease risk, recapitulates gluten-driven inflammation and increase in IELs, shown here on the right. How do we target these cells effectively? CD122 is a shared receptor through which both IL-15 and IL-2 signal. It's expressed on a range of immune cells: CD8, CD4+ T cells, as well as NK cells. Inhibiting IL-15 and IL-2 signaling inhibits subsets of these cells, reducing inflammation and tissue destruction, and targeting CD4+ T cells in particular has the potential for reducing inflammation that downstream immune responses, ultimately decreasing celiac disease consequences. What have we learned from clinical trial design? Lati glutenase, its mechanism of action was digesting gluten, was shown to have effects in protecting the intestine from gluten-induced damage, as well as protecting them from symptoms. However, when that was translated to a much larger study focusing on symptomatic treated patients, it failed to show benefit compared to placebo. What are the key considerations for a phase 1B trial design? Yes we need to include the traditional phase 1B gluten challenge design in patients with controlled symptoms and limited or no mucosal damage. If we're thinking about the phase 2B or phase 3 trials that are going to focus on symptomatic celiac disease patients, we must learn from what has happened with trials such as the lati glutenase that worked for a challenge in that population of patients doing well but did not translate into success in that much larger group of symptomatic treated patients. For immunologic mechanisms of action that effectively treat inflammation, if we can show that in a phase 1B trial that mucosal healing can result, this would provide a robust foundation for clinical development and later trials. What have regulators thought about celiac disease? The FDA has demonstrated a high level of enthusiasm in recognizing the need for additional treatments beyond the gluten-free diet for celiac disease. They've had significant public engagement with the conferences they've organized on outcome measures, their participation in advocacy meetings. They have articulated that in this key target population, they expect an agent to prevent symptoms of gluten exposure, as well as improvement of histologic injury, which will comprise two co-primary endpoints for a registrational trial. They also will require inclusion criteria that patients have active disease and that it's causing their symptoms. Thank you for your attention. Now we'll hear more exciting information from Paul in the next presentation. Thank you, Dr. Murray. In a typical gluten challenge study, celiac patients are controlled symptomatically on a gluten-free diet. They enter the study with a range of histology, including high villous height to crypt depth ratios above three to worsening levels of mucosal damage characterized by VH:CD ratios down to a level of two. The insights gained with gluten challenge studies have been valuable in providing a clear indication that a drug can prevent the onset or worsening of gluten-induced injury. However, this differs from the entry criteria and anticipated target population in phase 2B and phase three trials. The goal of these later-stage trials is to examine if a drug can promote mucosal healing in the setting of preexisting mucosal damage. We saw this difference as an opportunity to improve how phase 1B trials are conducted to potentially provide a better prediction of success in phase 2B. We have designed our phase 1B study to assess not only patients with baseline VH:CD greater than two, but to also include a cohort of patients with VH:CD ratio less than two to further assess if ANB033 will promote mucosal healing. Our global placebo-controlled multicenter phase 1B trial in celiac will enroll patients in Western Europe, Australia, and New Zealand. The two distinct cohorts will enroll 30 patients each, randomize one to one between ANB033 subcutaneous dose and placebo for a total of 60 patients in the study. The key inclusion/exclusion criteria distinguishing which patients are eligible for each distinct cohort is tied to the baseline VH:CD ratio. Patients in cohort one will have a VH:CD of greater than or equal to two and will undergo a gluten challenge to assess prevention of further mucosal damage, while patients in cohort number two will have a VH:CD of less than two to assess the ability to heal mucosal damage in symptom control patients. As this is still a phase one study, key assessments also include safety and tolerability in celiac patients, as well as PK and immunogenicity. The efficacy endpoints in the celiac trial assess ANB033 impact on both histology and symptoms. We expect to report data of ANB033 versus placebo on the change from baseline in the two common histologic measures, VH:CD ratio and intraepithelial lymphocyte count, as well as on qualitative assessments of celiac-related symptoms. For example, we will measure the Celiac Disease Symptom Diary, or CDSD, which is a validated patient-reported outcome measure. In the CDSD, patients track frequency and severity of key celiac symptoms, including abdominal pain, bloating, diarrhea, and nausea, in a daily diary to help gauge a change in their symptoms over time. Now let's review each of the two cohorts individually. Cohort one is a standard gluten challenge study that will enroll symptomatically well-controlled celiac patients with minimal evidence of mucosal damage or a VH:CD ratio of greater than or equal to two. We aim to enroll a good distribution of patients with histology scores distributed across the range from two to three, looking to assess prevention of further mucosal damage from the administration of gluten in patients who do not have normal histology. These patients undergo an initial endoscopy and then receive a dose of either placebo or ANB033 starting at baseline, then at week two and week four for a total of three doses. They will then begin a two-week gluten challenge through week six. The gluten facilitates a controlled induction of mucosal injury by administering a six-gram daily dose of a study-provided gluten cookie for each of 14 days. An endoscopy with biopsies will then be conducted at week six to evaluate any mucosal damage caused by gluten exposure on placebo, as well as assess if there was a prevention of injury in the ANB033 treated patients. Cohort two will enroll symptomatically controlled celiac patients who display persistent evidence of mucosal injury and have a VH:CD ratio of less than two. They will not be enrolled in the cohort one gluten challenge because the mucosal injury is already too significant to administer further gluten. These patients have histology consistent with patients who are nonresponsive to a gluten-free diet in the real world. These patients will also undergo an initial endoscopy and then receive a dose of either placebo or ANB033 at baseline, then at week two and week four for a total of three doses. However, after the final dose at week four, these participants do not receive the gluten cookie challenge. They will instead be followed for an additional eight weeks and will undergo their second endoscopy at week 12 instead of at week six, as in cohort one, as this will allow for a longer duration of mucosal healing after the last ANB033 dose. The model target tissue exposure is sustained above the IC90, at least through this week 12 endoscopic assessment. Demonstrating preliminary evidence of mucosal healing in a more histologically abnormal population provides additional complementary and supportive data to the results in the cohort one gluten challenge. While our cohort two trial design is innovative, there is a chance that patients will need to be treated for more than four weeks and/or need additional time beyond 12 weeks to see meaningful mucosal healing. Positive results in either cohort one or cohort two would support progression into phase two trials in nonresponsive symptomatic patients. We look forward to reporting the phase 1B data by the year-end of 2026. And now let me hand the call back over to Dan. Thanks, Paul. We'll close by briefly reviewing a substantial commercial opportunity in each of the diseases discussed today. Celiac disease affects over 2 million Americans. We will initially target patients nonresponsive to a gluten-free diet, projected by the early 2030s to be a quarter of a million patients in the U.S. Our conversations with physicians suggest they are seeking therapeutic options that address both the clinical symptoms and the underlying pathology, while payers understand the need for treatment and anticipate standard biologic pricing. Similar to IBD, growing physician and patient awareness, as well as the availability of approved therapies, are expected to meaningfully increase today's 30% diagnosis rate. With high unmet need, a large patient base seeking treatment, and anticipated reimbursement support, ANB033 represents a strong commercial opportunity for treating celiac disease in a market projected to surpass $4 billion. Further, initial approvals for patients nonresponsive to a gluten-free diet could expand the opportunity to the broader celiac population. Potential additional population of patients who are technically responsive to their gluten-free diets but find the strict lifestyle modifications challenging, as well, or in addition, as evidence continues to emerge that early tissue damage can be mitigated, newly diagnosed patients seeking to prevent gut damage may be potential candidates for treatment in the future. Similarly, we see significant opportunity in the EOE market, which has grown notably over the past three years and is expected to continue growing as disease awareness increases. Treatment options here remain limited. Half of patients do not respond to first-line treatment of proton pump inhibitors or steroids. For those who are biologically eligible, approximately 20%- 30% do not respond to Dupilumab, the only approved advanced therapy in EOE. Dupilumab, despite its weekly administration in this disease, is anticipated to sell an estimated $2 billion in 2025 in EOE alone. Even with only 50% of biologically eligible patients expected to be treated by 2030, the U.S. biologic market is expected to grow to approximately $5 billion in this time. As Martin demonstrated, ANB033's distinct mechanism targets both Dupi-sensitive and insensitive pathways, potentially making this an attractive market to pursue for development in both first and second-line advanced therapy. As I stated earlier, in addition to the potential advancement of rosnilimab into UCRA, we expect ANB033 to play an increasingly large role in our portfolio as we generate patient data in phase 1B studies. We plan to share top-line data from our celiac trial in the second half of 2026 and also plan next year to initiate a phase 1B trial in a second disease. Special thanks to Dr. Murray for joining us today and our team at AnaptysBio for their dedication to advancing innovative immunology therapeutics. Martin, Paul, John, Dr. Murray, and I will be available for Q&A. I'll now turn it over to the operator. Certainly. As a reminder, ladies and gentlemen, we ask that you please limit yourself to one question each. You may get back in the queue as time allows. Our first question comes from the line of Yatin Suneja. Please go ahead from Guggenheim. Hi, everyone. Thank you for taking my question. Excellent presentation. Can you hear me? Good. Okay. Hey, Dan. Yeah, a couple of questions for me. The first one is on the NK cell. Nice data on different subsets. Could you just talk about the relevance of total NK cell? If we do it, should we compare the NK cell data to see the potency of the molecule, or could that be used as a biomarker? That's one. The second question is also comment on the bioavailability between sub-Q and IV. The final question is for Dr. Murray, if he could comment on how would he adopt a treatment like this in his practice and who do you think is an ideal candidate for this treatment? Thank you. Thanks, John. Maybe we'll start with the question of Dr. Murray on just thinking about the program in celiac. Go ahead, Dr. Murray. That's an excellent question. As a gastroenterologist who treats patients with celiac disease, the only thing I have to offer them is a gluten-free diet. I have no drugs. On the other hand, if I treat patients with EOE, for example, or I treat patients with IBD, I've got a whole armamentarium of drugs, especially in the IBD field, for which I can choose. The availability of treatment drives our interest in treating patients. I believe that if we had a treatment such as ANB033, a subcutaneous drug administered intermittently, this fits right within the paradigm that gastroenterologists are very comfortable with: treating patients with chronic inflammatory disorders with drugs that address their inflammation. I think it would fit very well into that practice. I also think it'll drive their interest in the disease and greatly expand the awareness of the disease, the detection of the disease, but most importantly, enhance the management of the disease. The ideal type of patient, I would say, for this type of approach would be patients who have active disease with symptoms and inflammation despite doing their best on a gluten-free diet. That probably makes up at least 30% of the patients with celiac disease. Though it doesn't mean there aren't other groups beyond that that would also be potentially candidates for a comprehensive management of celiac disease or something that could provide comprehensive management. That's in a nutshell where I would see this. It would be a game changer for the management of celiac disease, but well within the capabilities of community gastroenterologists and all those who treat, say, for example, IBD or similarly even EOE now, where we use biologics fairly frequently, including in my practice. Thank you. All right. Then on the NK cells, we provided data both in the SenoTox studies as well as in our phase 1A. I would just say, we've been talking about this for a while, NK cells are particularly sensitive to the inhibition of IL-15. You don't need to be the most potent drug, whether you're an anti-IL-15 or CD122, to really see full coverage of reductions of the NK cells or specifically the CD122 expressing cells. What I would just caution you on, and I think this is also going to be true when you're looking at the effect of the various T cell subtypes or the IELs over time, is to just make sure that you're looking at either CD122 expressing of that cell type or the overall cell type. As you saw in the SenoTox work, where effectively all NK cells are CD122 expressing, we bring those down to 100%. In humans, you see pretty much equivalent coverage of the CD122 expressing, which results in somewhere in the 70 to 80% of overall NK cells. We think this is pretty consistent really across the entire landscape and not the area of differentiation when it comes down to it. Next question? Certainly. Our next question comes from the line of Joseph Thome from TD Securities. Your question, please, TD Cowen. Hi there. Good afternoon, and thank you for taking my question. Maybe one for Dr. Joe Murray, one for the company. Dr. Murray, do your patients present with the same type of symptoms? I know nausea, bloating, diarrhea were indicated, but I guess is there a typical disease course, particularly for your patients that maybe are refractory to a gluten-limited diet? For the company, can you talk a little bit again about what you're looking for for success? Do you want to have success in both cohort one and two to move forward? It sounded like maybe you would look at either, but you also brought up the lattice glutenase example, which was kind of looked to be helpful in preventing gluten-induced injury but not in healing established disease. I'm just looking to better understand what you're looking for there to move it forward. Dr. Murray, why don't you kick off? If you wouldn't mind, feel free to give your opinions on the second question as well, and then we'll add on to you. Dr. Murray, you are on mute. Can you hear me now? Yes, we can. Yes. Okay, good. Sorry. The typical patient that I see with nonresponsive celiac disease, the most common symptoms relate to abdominal symptoms. Abdominal pain, bloating, nausea, of course, would go along with that. There is a significant subgroup who have diarrhea as part of their symptomatology. That's still a minority of those patients, but it is an important symptom for those patients. Fatigue and headaches, of course, are two other symptoms that are also quite common in celiac disease and are a little bit harder sometimes to capture. There are a whole variety of other symptoms that patients complain of, but it's really captured within that group of abdominal symptoms. The symptoms vary tremendously from day to day. They can be nonexistent on one day and severe on another day. A measurement device like the CDSD, more recent version, the 2.1 version, captures both severity and frequency of these key symptoms to really assess where they're at. That's a fairly typical group. Those are patients who are, I would say, intermittently miserable because of their symptoms or quality of life is impacted. And the second question, I forgot. Just thinking through the different cohorts in our phase 1B trial, what you'd expect to see as a result that would excite you. Oh, okay. When I think of this phase 1B design with these two cohorts, one, it takes advantage of patients who typically would be excluded by their beginning biopsies showing too much damage. It keeps them in. That's great as an investigator. I love to see that. It also identifies a group of patients, which we think are quite common, that is, people who have fairly minimal symptoms but still have inflammation. That second cohort provides an opportunity to show benefit or impact of this approach, targeting CD122, with regard to that ongoing persistent inflammation. If we see that type of benefit, that really helps increase the likelihood of success when we target that population, which the FDA has said has to have not only symptoms but evidence of inflammation to be included in those later phase 2B or registrational trials. The other part, of course, it is absolutely important that this agent or agents like this can prevent the impact of gluten. That's, I suppose, what's exciting for me, the fact that these CD4+ effector memory cells can be impacted by these treatments. Those are cells that are long resident within patients with celiac disease. Even though they've been avoiding gluten for a long time, they get exposed to gluten, and they get a very immediate response. We want to see that also. I want to see that also blocked, and I expect that we should see that blocked with this type of approach targeting these particular cells in celiac disease. Both of them happen, and that would be an amazing result to see both. I won't say amazing isn't surprising, but would be a very strong result to see both of those happen. I expect we should see signals both for the protection of injury in the patients with gluten challenge, as well as improvement of patients who've got inflammation at entry. Yeah, it's Paul. Dr. Murray, I think you said it very well. I don't think I have much more to add and would agree that we would hope to see signals in both of those cohorts. I think we're quite pleased that we'll have the opportunity to study both the gluten challenge as well as those who are not undergoing gluten challenge and already have preexisting injury to see if we can detect at least initial healing in that first 12 weeks. Certainly. And our next question comes from the line of Alex Thompson from Stifel. Your question, please. Hey, great. Thanks for taking our questions. I think the first one on ANB033 specifically, is there any residual effect or function here with depletion of the relevant cell types based exclusively on its removal of the proliferative survival pathway, like with the pure IL-15 targeting? In terms of the phase 1B doses, how confident are you in the PD translation to patients here and that you'll see the relevant effects on these cell types after just three doses? Thanks. Alex, do you mind just repeating the first question? I'll make sure we address it the right way. Is there any residual effect or function with ANB033 in terms of cell killing of the CD122 positive cells, or is this just purely blocking the survival pathway here like the IL-15s? Yeah, thanks for the question. ANB033 was designed for high potency as a non-depleting antibody. Perfect. Helpful. Thank you. Thank you. Our next question comes from the line of Yasmin Rahimi from Piper Sandler. Your question, please. Thank you so much. Thank you for the excellent presentation and very thorough. The first question is for our Dr. Murray. Given the size of the two cohorts, one and cohort two, do you think it's sufficient to get a definitive answer to establish sort of efficacy? Can you also help us understand when we take this data from a small cohort study to then towards a registrational path, what that translation looks like? Of course, these are two tough questions since we've not seen the treatment effects, but would love to kind of help us understand the importance of these two cohorts, one and cohort two, design in its later translation to a larger phase three design study that could gain approveability. Terrific question. As I think about the size, these are small cohorts. It is a phase 1B trial, so it'll be the first time patients with celiac disease will be seeing this agent. By their very nature, it's going to have to be a small cohort, so you cannot be absolutely definitive. Of course, one would expect with a potent agent to see a very strong signal. If we take that cohort one, the challenge of six grams a day for this two weeks really should push the response. A potent agent with a type of dual, I would say at least dual approach or CD4+ T cells as well as CD8+ T cells, we should be able to see protection from inflammation with the intestine. There's going to be some heterogeneity. There's always some variability between patients. But by and large, I think there's a good chance that we would see a clear signal. The second cohort, again, it's a small cohort. They're small numbers, and there is, of course, an issue with this that you can have on the placebo side. You may have what's called the Hawthorne effect, where patients coming into a trial do an even better job of avoiding gluten. There'll probably be patients who've been on a gluten-free diet for at least a year and probably much longer. Many of these studies' patients have been on a gluten-free diet for five years, so they may already be fairly stable. So a potent effect on inflammation may well give us at least a trend to support that. Results from that second cohort, if it indicates the possibility of benefit in terms of inflammation, what that then informs us is that when we think about, say, sample size for a phase 2 study that's focusing on these nonresponsive celiac patients who have inflammation, we may be able to reduce maybe the total numbers required. There are other strategies to deal with the Hawthorne effect that are appropriate for a phase 2 and maybe even a phase 3 trial, such as doing simulated gluten exposures, for example. I think both of these cohorts, even though they're small, have the potential for providing us with a fairly solid foundation upon which to design those much larger phase 2 studies that will be focused on this high-need population of nonresponsive inflamed patients. Thanks, Dr. Murray. I'll just maybe add on a little bit. We do have about 15 subjects in each cohort in each of the two, so 30 subjects per cohort. There is an adequate number to see a signal and detect that. We are 80% powered to see the mean change from baseline into the VH:CD ratio. This is pretty standard for a phase one trial size. I would say we're comfortable with where we're going and looking forward to the results over time. Thank you. Thank you. Our next question comes from the line of Andy Chen from Wolfe Research. Your question, please. Thank you for taking the question. On slide 29, you say that you have more than you're modeling IC90 in CD8+ T cells, but you don't mention anything about ILC2s or NK cells or CD4+ T cells. It's odd to me because on the next slide, you seem to have greater impact on NK cells. I'm just curious if you have also modeled IC90 for the other immune cell types. On a related note, because you're seeing full receptor occupancy in healthy volunteers, but we should have much higher immune infiltration in disease tissue, do you know receptor occupancy on different types of CD122+ immune cells in patient tissue? Thank you. Martin, why don't you just walk through a little bit of the differences and how we look at the various immune cells and how we target each of them? Yeah, thanks. It's a pretty complicated question. Let me level it up a little bit. We designed ANB033 with potency in mind. This is within the mindset that the cell types we're targeting each have a different sensitivity to the cytokines IL-15 and IL-2 and hence a different sensitivity to ANB033 inhibition. Let me start with the NK cells. These are particularly sensitive to IL-15 inhibition. As Daniel Faga said earlier, it doesn't take a lot of inhibition here to decrease the NK cells almost entirely. Yes, we modeled the IC90 off of this, but it's so easily achieved. We don't believe the NKs are sort of the primary mediators of disease in celiac or in eosinophilic esophagitis (EOE). We spent most of our time modeling for the CD8+ T cell biology. So CD8+ T cells, which are very similar to the intraepithelial lymphocytes that we're interested in for celiac, signal through the intermediate affinity receptor. And you need a pretty high potency antagonist to target these to the IC90 that we're planning. In particular, the IC90 in the tissue that you're interested in, the small intestine for celiac. We also looked pretty closely at memory CD4+ T cells. These signal through the intermediate and the high affinity receptor for IL-2, and you need a very potent CD122 antagonist to inhibit these very potently, particularly again in the tissue. We believe, as we showed in some of our biology slides, that the CD4+ T cells are going to be some of the root cause of the disease, and we want to target those. We also spoke briefly about Tregs. Tregs express the high affinity receptor, but they're very unique, and they express also very high levels of CD25, which allows them to capture IL-2. And so they're particularly resistant to CD122 antagonism. Getting back to your question, we spent most of this focus modeling the IC90 for CD8+ T cells because we believe that's the primary effector cell that we want to hit in celiac in the IEL compartment. We also believe CD4+ T cells are very important, and we do believe we'll have a strong on-target engagement there. Yeah, I'll just add one more point. We mentioned we saw a dose response in the phase 1A. We're showing you representative doses that hit the max impact across the CD8 to the NK cell. We had enough data here between the cytotox work and the phase 1A to do the right modeling to, at least in our eyes, believe we're going to get enough antibody into those compartments in the gut. That's the other important part. When we get there, we've just shown you that we're potent. Thank you. Our next question comes from the line of Anupam Rama from JP Morgan. Your question, please. Hi guys, this is Priyanka on for Anupam. Just a quick question from us. What characteristics or biological responses would you point to as the most important to say there is mucosal healing in the celiac clinical trial? Would it mostly be the VH:CD ratio change from baseline, or is this more about the totality of data? Dr. Murray, you want to give some perspective? Yeah, I'll have a go at that one. I think for most trials that have included histology, we've kind of relied on the VH:CD ratio as the primary measure of mucosal health. Now, of course, that's a very crude measure, but it is reproducible, and there's a reasonable degree of precision, and we know how the mucosa deals in terms of a challenge, the response to a challenge. That would still be the primary one. Intraepithelial lymphocyte count, as it were, is also quite measurable, and also has got reasonably good inter-observer variability. The precision is good on that also. That's a good secondary one. There are, of course, lots of other inflammatory markers you could look at, breaking out cell types, et cetera. Really, the histologic, I think for virtually all studies thus far, they've taken the villous height to crypt depth ratio and the intraepithelial lymphocyte count as primary and secondary measures for the mucosal health, as it were. We're also collecting symptoms, or there will also be symptoms with the CDSD. It would be great to see a signal of protection from gluten-induced symptoms in cohort one. There's probably not going to be much of a signal to see in cohort two in terms of symptom improvement because of the way they're recruited to begin with. Yeah, and just to add on to that, it's very standard, and we would be doing this as well in terms of reporting out VH:CD, the change of VH:CD versus placebo, as well as the change in the intraepithelial lymphocyte count. Those are standard, I think you see in every trial where we'll be reporting those across both cohorts. Thank you. Our next question comes from the line of Martin Fan from Wedbush. Your question, please. Hi, thanks for taking my question, and congratulations on the progress. I have two questions here. One for Dr. Murray. What percent of celiac patients would you say have comorbidities, and do you think this could be a reason to choose immune modulators over celiac-specific approaches such as tolerization or barrier modulators? To the AnaptysBio team, curious about what would be the trigger to initiate development in eosinophilic esophagitis (EOE), and when we might expect to hear any confirmation on development plans for the second indication? Okay, I'll take the first one. With regard to comorbidities, probably somewhere in the range of 10%, 10 to 15% of patients with celiac disease have comorbidities that might impact. For example, we see a proportion of patients who also have microscopic colitis, an inflammatory condition of the colon that there is no, I mean, really approved therapy for. If I had a potent anti-inflammatory that targets intraepithelial lymphocytes, cytotoxic T cells, CD4+ T cells, I'd certainly be very encouraged to consider it. We also do see some overlap with eosinophilic esophagitis (EOE), which is also of interest to the program. And then why not use something that could hit both? Those would be very, very specific categories. By and large, the other comorbidities are things typically that are consequences of celiac disease. There is a small proportion of patients who have, say, IgA deficiency. That's probably no more than 2 or 3% of celiac patients. I don't see any reason why that would not be a good population to use an approach like this in. Other consequences like osteoporosis, or the risk for malignancy is certainly there. We know chronic inflammation can increase the risk of malignancy, especially in older patients. Something that focuses and suppresses inflammation, I would say, would probably be a good thing in patients where we might be thinking of ultimately a risk of untreated chronic inflammation long term. So is that what you were getting at? Yes, definitely. I'm also curious about other approaches for celiac disease, the ones that are specific, such as gluten tolerization or barrier modulators. Do you think these comorbidities might give rationale for choosing an immune modulator such as? Yeah, that's an excellent point. I'm not sure that we have become sophisticated enough in the field to actually consider that because we haven't actually got therapies, but I know in other diseases like IBD, we frequently modify our choice of approach dependent on comorbid disorders. When I think about the question you've asked in terms of choices, if I have a chronic inflammatory disorder that's mucosally based, for example, the colitis that I mentioned, definitely I would tend to use or choose an anti-inflammatory, something that's directly targeting inflammation, as opposed to something that's, for example, breaking down gluten, for example, or tolerization. We know that in the context of the particular comorbidity of microscopic colitis in a celiac, the microscopic colitis does not respond to a gluten-free diet usually. Doing something that just blocks the effects of gluten is probably not going to help that comorbid condition. This is a little further down the pike, probably post-registration. I'll just add to some of this and answer your second question. I think as we think about targeting celiac disease and treating inflammation, just like in a lot of other autoimmune diseases, you want to target the inflammation to see disease modifications. Same rationale here. Dr. Murray did a nice job of really highlighting a lot of broader GI diseases that we've listed on some of our slides today. You're asking about EOE specifically and some of the triggers, and we laid out a case. We clearly don't work here in EOE in terms of the biology and some of the modeling. There's also work that exists in other diseases. We didn't have time today to get into all the derm disorders. There are others working currently or actively in the space of the IL-15 path or the CD122 blockade. In terms of EOE specifically, we're assessing how do you run an efficient phase 1B design, one that's similar as in celiac, one where you can show benefit on both histology in terms of EOS reductions, as well as symptomatic improvement. The exact same approach we're taking in the celiac disease. Can you show data in the phase 1B trial that adequately de-risk the phase 2? We're doing something different here. It would give us more of an evidence-based approach that would de-risk celiac in phase two. We're looking at this the same way in EOE, where we've seen mechanisms that reduce EOS but don't actually impact symptoms. It's the same idea. We're assessing it right now. There are other choices, and we'll make a decision in 2026 in terms of EOE or some of these other diseases. We're also watching this space, and we are going to see data in this space in some of these other diseases that could impact what the second indication will be. Thank you. Our next question comes from the line of David Reisinger from Leerink Partners. Your question, please. Hey, thanks very much. Congrats on the progress. This is Edward speaking on behalf of David Reisinger. Two questions, please. In terms of the onset of action, how should we think about ANB033 against other IL-15 targeting agents, and should we expect targeting CD122 to translate into deeper or more durable responses down the line in celiac disease and other indications? The second question is, could you please comment on Forte's phase two celiac disease trial? What are the key considerations you will highlight ahead of the company disclosing data next year? Thank you. You want to address that first, Martin. I can briefly take the first part. The anti-IL-15s are going to target the IEL compartment in celiac in that box that we had on the diagram. The CD122 antagonist is going to also do that, but it's going to antagonize IL-2 signaling as well. That benefit on top of the IL-15s gives you the ability to also reach the CD4+ T cells and the biology that that unlocks. Very important to addressing the root cause of gluten-sensitive disease in celiac. I would just say that you can see from the phase 1A data, at least in the periphery, we're seeing very rapid response, and this is off of SAD, so single dose that has long ED. I'm not sure you'd be faster than what we're seeing in terms of the impact of all the cell types that we're discussing. I'll leave it to others to comment on competitive data and timelines and catalysts. Thank you. Our next question comes from the line of Emily Bodnar from H.C. Wainwright. Your question, please. Hi, thanks for taking the questions. I was curious if you could comment about the dosing you're planning to use in the phase 1B. It looks like you're potentially using a single dose. Any commentary on your confidence in that dose being effective? Are you planning to use the same dose for both cohorts, or might it make sense to use a higher dose in the more severe patients? Thanks. Yeah, thanks for the question. We are using the same dose across cohort one and cohort two. As we walk through, the patients will receive three specific doses in each cohort at baseline, at week two, and at week four. As we described earlier in the Q&A session, we've done the modeling I think we need to do and feel confident that we are administering enough drug to have the appropriate amount of antibody get into the gut, into the tissue. We should be able to see the effect we're looking for, at least on a biological level. When you're going in with one dose, you take the approach where you're not going to miss on being too low. I think that's all we're going to comment on in terms of the specific dose at this time. Thank you. Our next question comes from the line of Derek Archila from Wells Fargo. Your question, please. Great, thanks for taking the questions. The first one's for Dr. Joe Murray. I just want to be clear. When you say a patient's not responding to a gluten-free diet, are you basically saying that they continue to have active inflammation in absence of gluten, or is it because of symptoms due to the mucosal damage? I just didn't know if it meant that they were just not compliant, or is it actually just irreversible damage? One for the company, just in terms of what we should expect, I guess, from like a placebo response on histology and PRO measures for the types of patients that we're seeing evaluated in cohort one and cohort two. Thanks. So I'll address the question. Excellent question on how we kind of think about those patients with non-responsive disease, or what's also been termed active celiac disease despite people doing their best on the gluten-free diet. The gluten-free diet is just not a great treatment. It is extremely burdensome. One study which looked at comparative burdens of care suggested celiac disease is the same burden of care as end-stage kidney failure, which is really pretty bad. That's because the entire burden of care is on the patient. It's a hard burden to carry. In our modern living, there is gluten everywhere. We assume that most patients with celiac disease are getting some gluten in their system and that gluten can cause both ongoing symptoms and inflammation. The FDA has made it clear in their draft guidance and in discussions, public discussions, that they really want to see this treatment for an effective treatment for this population, that is people who have got ongoing symptoms related to their celiac disease and inflammation determinable by biopsies, and that both of those things have to be improved for them to consider a therapy effective. I think when we think about it, there are some patients who are doing symptomatically very well, but who still have significant damage. Then there are patients who have very bad symptoms that are very intermittent but are triggered by gluten exposure. As we discussed earlier, even patients who are healed get gluten. They get this significant production of IL-2. They get symptoms. This happens within hours. Something that could retard that effect or that could prevent or reduce those numbers of CD4+ effector memory cells and block that IL-2 effect could be a game changer in terms of helping patients with those types of symptoms also. There are other cohorts of patients beyond that, but that's really, I think, the most important needed population that needs treatment. Hey, Dr. Murray, just in terms of that second question that was asked regarding placebo and the impact, maybe you can give some perspective on how we're administering the six grams of gluten. Is that enough? What do you expect to see there, and maybe relative to other studies? Yep. Six grams is a substantial amount of gluten. For a celiac patient in their normal lives to face that, that's a lot of gluten. That's not a little gluten. It will produce some symptoms. With careful management of those patients in expert centers, we can coach patients through those couple of weeks of gluten challenge. Usually, the symptoms are worse with the first and second dose. It is a good enough dose to overcome any behavioral change that may occur due to participation in the diet, more than enough to drive both symptom generation related to gluten as well as changes of inflammation that are measurable with quantitative histology. Placebo patients, of course, they're placebo patients. We have to support them. Recognizing them that they're going to get symptoms. Patient populations are very motivated. The celiac population are very motivated. They are very enthusiastic for participation in studies. They often see it not only as a service to themselves, but as a service to their family members who may have celiac disease. In addition, you want people to also stick with not only the study, but stick with the gluten challenge. AnaptysBio have laid out a very careful plan for counting the wrappers too, giving them a solid food, real food article that contains a measured amount of gluten, not a slurry of basically gluten powder mixed with something, maybe something to disguise it, but rather by using something that mimics real food, which then mimics the type of exposure that somebody would normally get with gluten within the digestive system. Measuring gluten peptides as a way of verifying the patients actually took their gluten and letting them know ahead of time that you're doing that. Messaging with the patients, contacting the patients on a regular basis operationally will help keep people encouraged, keep them in the study, and keep following the protocol. I think with all of those measures, a high likelihood of successful conduct of this study. Yeah, I'll just add to that. In cohort two, as we mentioned, certainly those patients have a substantial amount of damage given that their VH:CD ratio is less than 2. You're really looking for healing in that population over the course of that time period in that 12 weeks, and you're not going to really expect to see much happening in the placebo subjects in that setting. Those patients will, of course, probably know that they have got damage, and they'll be very motivated to remain in the study and see if they improve. I have to say, as an investigator, I really hate to screen fail somebody because they've already done a run-in phase by the time they get to getting their biopsy. They get very disappointed, and I'm disappointed. I think this novel design of keeping those people in as cohort two, who otherwise would have failed as a late screen failure with the attendant expense, et cetera, that occurs with that, is a very good positive from a trial conduct perspective. Thank you. Our final question for today comes from the line of Etzer Deraut from Barclays. Your question, please. Thanks for taking the question. I guess my question, Dr. Murray, you can comment on this as well, but just wondered if you've had conversations with clinicians on the chronic usage of ANB033 versus episodic dosing in celiac disease, and does the phase 1B result start to maybe answer that question? Thank you. I will confess that the thinking, at least in celiac disease, has evolved from a therapeutic perspective. I go back only 15 years, and most gastroenterologists, even most people in the celiac space, would really not be thinking about chronic therapies for celiac disease beyond a gluten-free diet. It took our patients to really inform us about how life was not so hunky-dory with their living with what we thought was a great treatment, as we as doctors thought was a great treatment as a gluten-free diet. It really wasn't. There is an appreciation that these patients have a chronic inflammatory disorder with substantial symptoms. The treatment we're currently giving them is not particularly effective in that cohort, and it's associated with a significant burden. There is an appreciation that we need a chronic management plan. Now, whether that management plan incorporates daily therapies, weekly therapies, monthly therapies, it does really devolve around the notion that we need to have chronic management. It's not likely to be a once and done or a sharp shock treatment will then reset people. That's unlikely because we do know in celiac disease that the memory for gluten, the immune memory for gluten, is very deep indeed. That's why these effector memory cells, these CD4+ memory effector cells that respond to gluten, are a particularly attractive target to deplete and disable, as it were, because they're where that memory resides. For that reason, at least when I speak with most of my colleagues, we're thinking about chronic management. My prediction is that if we get a treatment that is potent and that suppresses inflammation and protects people from symptoms of their disease, this will be treated much more like what I call IBD3, a third inflammatory bowel disease, and that we'll be thinking of it as a chronic inflammatory disorder that requires management, not that dissimilar from other inflammatory disorders. I'll just add to finish up. In the phase 1B trial, these are obviously shorter course trials. They're not meant to imply it's three doses and you're done. You're done for life, right? It's not that. I think we are taking advantage here in cohort two as we look at three doses through week four and then doing the endoscopy through week 12, that we are relying on the complete data we have to date where we do have longer-term BD effects of the target cells of interest, specifically the CD8+ T cells and CD4+ T cells. We are going to get an assessment there in four weeks of treatment and then at week 12, some initial basis of healing. This will all inform phase two trials, which will be longer course treatments over a longer time horizon, six months plus, six months to a year. Thank you. Thank you. This does conclude the question and answer session as well as today's program. Thank you, ladies and gentlemen, for your participation. You may now disconnect. Good day.