Investor Update Transcript - ZBIO 2026-09-29

Operator

Good morning, and welcome to the Zenist BioPharma, a Bexlamab IgG4 RD investor event. At this time, all participants are in listen-only mode. There will be a question-and-answer session following the prepared remarks. Please be advised, this call is being recorded, and a replay along with the presentation slides will be available on the investors section of the company's website following the event. I will now turn the call over to Abby Gray, Director of Investor Relations. Please go ahead.

Abby Gray, Head of Investor Relations

Thank you, and good morning, everyone. Before we begin, I'd like to remind you that today's presentation contains forward-looking statements, including statements regarding the potential approval and commercial launch of the Bexlamab and IGG-4RD, the timing of our regulatory submissions and clinical readouts, and our expectations for the market opportunity ahead of us. These statements involve risks and uncertainties that could cause actual results to differ materially from what we discussed today.

Leon O. Moulder, Jr., CEO

I would encourage you to review the full disclaimer on this slide, along with risk factors described in our most recent annual report and quarterly report five of the sec for a complete discussion of those risks i will now turn the call over to lani molder our founder and ceo thank you abby abby joined us a few weeks ago as our director of investor relations and i know she looks forward to meeting and interacting with all of you thank you all for joining us for our abexlimab igg4 related disease investor event today. We'll walk through the unmet need within the current IgG4RD treatment landscape, the commercial opportunity ahead of us, and how we are preparing to execute what we believe could be a transformational launch, both for patients living with this disease and present us. We're also very pleased to have with us Dr. Guy Katz from the Division of Rheumatology, inflammation, and immunity at Mass General Hospital, who will share his perspective on IgG4-RD and the unmet patient needs, along with the Indigo study results. Joe Farmer, our president and chief operating officer, will then walk us through the market opportunity and our launch readiness in detail. We will then open up the line for questions. While we are laser-focused on executing a successful abexlimab commercial launch, if approved, we feel that is important to highlight how we are well positioned regarding our overall rheumatology and neuroimmune pipeline, which spans multiple indications with recognized regulatory paths to approval and significant commercial potential. Of note, we are expecting top-line Phase II results from the Sunstone study of abexilumab in SLE and pharmacokinetic safety and tolerability data for ZV021, our oral IL-17 AA-AF inhibitor, both in the fourth quarter of this year. While we are very excited about the opportunities across our broader pipeline, our focus today is on IgG4RD and the upcoming anticipated launch of Ibexlimab. We hope you will join us for a deeper dive into the Sunstone SLE study and our IL-17 inhibitors ZBO21 at our R&D event later in October. Zenith's leadership and our overall team are deeply experienced across all aspects of drug development and commercialization. We are not a team learning what a drug launch looks like in real time, rather a team that has seen where launches go right, and importantly, where they may quietly go wrong. We believe we have a validated launch playbook and are ready to execute. Before we get into the specifics of our launch planning, I want to spend a moment on what makes a successful rare disease launch. In our experience, the disciplined execution of a strong launch plan is what sets a company and a launch up for success. We've built our plan around five interconnected components. First, recognize and refer sooner, shortening the path to diagnosis instead of waiting for IgG4RD patients to find their own way to a specialist. Second, find every diagnosed patient through data-driven identification, not guesswork. Third, earn physician conviction with evidence that is genuinely differentiated, not just differently marketed. Next, remove access friction. So, a written or inputted prescription can actually become a filled one. And finally, the link most companies underinvest in provides support that extends beyond the prescription because a patient who starts therapy and quietly stops it months later isn't a launch success. This connected continuum is what can turn a good drug into a successful launch. We believe IgG4RD represents a substantial market, assuming approximately 50% of the currently diagnosed and managed patients are addressable and the benchmark price of the approved therapy for this indication, we estimate the U.S. market opportunity approaches $4 billion. We and others estimate there are 30,000 to 40,000 prevalent IgG4-RD cases in the U.S. today. Our analysis of claims data indicates approximately 25,000 patients are currently diagnosed and managed. Of this population, we estimate that the flare frequency and or the potential consequences of flares results in approximately 12,500 patients eligible for ongoing maintenance therapy, and that's the core of today's addressable opportunity. It is expected that diagnosis rates, awareness, and referral patterns will keep improving with the availability of approved therapies. We believe Bexlimab can be positioned as the preferred first-line therapy for the majority of IgG4-RD patients, and this is supported by four key areas of potential differentiation. Efficacy and safety data that stand on their own, a mechanism that is genuinely different, the reversibility and flexibility to potentially pause around vaccination or intercurrent illness, which a B-cell depleting therapy cannot offer, and the convenience of at-home weekly dosing. That combination is why, in our market research, approximately two-thirds of treating physicians told us they're extremely likely to prescribe a Bexelumab and one-half indicating they were prescribed at first line, and that is before any marketing or sales promotion. At launch, there will be two clear prescribing paths. The first is active flares, newly diagnosed patients presenting with a flare and previously diagnosed patients who are not currently receiving treatment and are flaring again. Both are moments when a physician is actively making a treatment decision. The second is active treatment where patients are currently receiving a biologic and cycling back to their physician prior to scheduling their six-month infusion. Each of those visits is a moment where a physician will have the opportunity to introduce a new drug to patients, and we believe our profile gives them a compelling reason to potentially implement a switch that is the difference between hoping for adoption and intentionally impacting it with that I'll now turn the call over to Dr. Katz who is not only an expert in this disease but manages numerous patients living with IgG4RD thank you Dr. Katz for joining us this morning and sharing your thoughts with investors on IgG4RD and the unmet patient needs, along with the INDIGO study results.

Dr. Guy Katz, Analyst — Rheumatologist, Mass General Hospital

Thank you very much, Lonnie. It's such a pleasure to be able to speak with you all today about IgG4-related disease. What we'll do is we'll discuss some overall concepts about how IgG4-related disease presents, how their diagnosis is made, and some key areas of unmet need. And then we'll spend some time talking about the specifics of the INDIGO trial and the First, let's start with a—and next slide, please—first, let's start with a definition of the disease. So, IgG4-related disease is a systemic, chronic, and progressive immune-mediated disease. We think of it as a fibroinflammatory disease, meaning that there is a component of inflammation and a component of fibrosis or scar tissue deposition that results from the inflammation. And this is a disease that can affect nearly any organ in the body. There are a few important exceptions, but almost every organ can be affected. It's a chronic disease. The vast majority of patients will have active disease if they're not undergoing treatment. And after they undergo treatment, the vast majority of patients will eventually relapse after treatment is discontinued. And this is a disease that leads to very frequent irreversible fibrosis, organ damage, and is even associated with increased mortality. Some of the specific features that I would mention about it, it's typically multi-organ. The majority of patients have more than one organ involved, and some patients can have five, six, seven, eight, or even more organs than that. It is a relaxing disease, as we discussed. Most patients will have a relapse at some point after they come off treatment, and some patients might even relapse on treatment. And very importantly, there's a really substantial subclinical component to this disease, which we'll discuss in more detail soon. One of the ways that we come to the diagnosis is through histopathology. So biopsy is an important element of the diagnosis in many patients, not all patients. And on this slide, you see the typical histopathologic features that we associate with IgG4-related disease, which are a dense infiltration with lymphocytes and plasma cells. Most of those plasma cells, or at least many of them, staying positive for IgG4. We see very frequent fibrosis or scar tissue, and in IgG4-related disease, it's very often in this typical storoform pattern. And obliterative phlebitis is the third typical hallmarked phylogic feature that we see where there's inflammation of the veins within the tissue that's severe enough that it it obliterates the lumen or the inside portion of the vein. We often see elevated serum IgG4 concentration, which is part of the reason that the disease is called what it is. And imaging is an important part of how we make the diagnosis because we see very typical either enlargement or massive in the expected distribution depending on the organs that are involved by the disease. So, as I mentioned before, this is typically a multi-organ disease, and almost every organ in the body can be affected. The figure on the left side of the screen demonstrates the multi-organ potential of the disease. And you can see that there are certain organs that happen particularly commonly, and the most common manifestations are enlargement of the lacrimal or lacrimal glands, which are the tear glands, which are on the side of the eye, as well as the major salivary glands, the submandibular glands, which are just under the jaw, and the parotid glands, which are just behind the jaw. And when these are involved, typically they present as painless and symmetric enlargement of the gland. Very often, patients don't even realize that they're enlarged. And this is one of the few manifestations that even during active disease, when it's asymptomatic, the propensity for damage is not particularly concerning. There can be an increased risk of dry eyes and dry mouth. But with the exception of those, just about every other manifestation of the disease with or without symptoms has the potential for really significant and meaningful damage that can happen to the patients over time. After the glands, the next most common organ that's involved in the disease is the pancreas, and the pancreas by far is the most commonly damaged organ in the disease. When it presents, it can present either with enlargement of the pancreas or occasionally can present with a pancreatic mass, so it's not uncommon for these patients to be misdiagnosed having pancreatic cancer, unfortunately, before they come to a correct diagnosis of IgG4-related disease. And once they have the diagnosis, it's actually very common for the pancreas to fail as a result of the inflammation from the disease, with about half of patients developing exocrine pancreatic insufficiency, where the pancreas is not able to produce enough digestive enzymes to digest, to allow the patient to digest the food that they eat, or to also about half develop diabetes, which is a result of the pancreas' function of producing insulin being compromised by the disease. And the last manifestation that I'll mention is one of the most common and typical manifestations of the disease is retroperitoneal fibrosis, and you can see a picture of that on the bottom right of the screen here. where there's this soft tissue that encases the aorta in the retroperitoneum, which is the posterior aspect of the abdomen. And that is often asymptomatic until it leads to compression of structures in the area. And the most common complication of that is when it obstructs the ureters, which are the tubes that feed urine from the kidney into the bladder, and it's very common to see backup of urine into the kidneys, which can actually be a medical emergency when that occurs. This slide shows that there are manifestations that can be seen in many other organs, and this is not a comprehensive list by any means. So it's important to recognize that the potential for damage in this disease is really substantial. Next slide. Another aspect that really can contribute to the very frequent damage that we see is that this is a very frequently subclinical or asymptomatic disease. And at its surface, that sounds like a good thing. It sounds great that patients don't have to suffer when they have active disease, and of course, that's true. But the flip side of that is that when patients don't have symptoms, they're very often ill but don't realize it. And this is an important differentiator between IgG4-related disease and many other autoimmune diseases, where typically when patients have active disease, they know that they're ill, even if they don't know what the diagnosis is and can't necessarily say that, you know, maybe they have inflammatory arthritis or interstitial lung disease, but they know they don't feel well. The same isn't always true in IgG4-related disease, where patients can have even severely really active disease and have little to no symptoms, but that activity is still causing progressive damage to the organs even if the patients don't feel it at the time, which is why we see such a large burden of damage, irreversible damage to organs, even very often the first time we meet a patient before they even have their initial diagnosis. And this schematic shows that over time, very early on, there may or may not be symptom onset while there is ongoing active disease. And then by the time the patients come to a diagnosis, they very often had active disease. And it's not uncommon for me to meet patients when we, in hindsight, are able to recognize that they likely had evidence of active disease for several years or even over a decade. Next slide. We don't know the true prevalence and incidence of this disease with 100 percent certainty, and that's for several reasons. One is that there is still under-recognition on the part of providers, where many providers are not recognizing the typical manifestations of this disease and not coming to the right diagnosis. And two, it's not until recently that we had an ICD-10 code for IGG-4-related disease. So claims-based analyses really only cover the past couple of years, and we don't have anything from prior to that. The data that we do have, which I think most of us agree likely underestimate the true prevalence and incidence of the disease, if anything, indicate that the prevalence is about 5 per 100,000 in the United States, and incidence of about 1.4 per 100,000 patient years in the United States. In Japan, the prevalence is perhaps a little bit higher, but again, it's a little bit hard to know with 100% certainty, and I do suspect that at least the United States numbers are likely an under report from under diagnosis and from many patients who are sick but don't have the right diagnosis. Next slide. The pathophysiology of IgG4 related disease is something that we've learned a lot over the past decade and a half or so since the disease was first named and we started really paying attention to the immunology of the disease. And I won't go through this slide in excruciating detail, but I'll summarize it as such. So as is the case with most autoimmune diseases, we suspect that there is some antigen that leads to activation of a naive B cell. Once that naive B cell is activated, it then communicates with a T cell, and that relationship between the B-cell and T-cell leads to downstream immunologic effects that range from activating plasma blasts and plasma cells, which are ultimately the cells that produce the IGT-4 that we're measuring in serum. There's activation of CD4-positive cytotoxic T-cells, and there's kind of downstream effects on fibroblasts and myofibroblasts, as well as macrophages, all of which lead to the prominent fibrosis that we see. So it's a combination of T-cells, B-cells, and macrophages and myofibroblasts that ultimately lead to the tissue damage and the fibrosis that we see in the disease, but it all really begins with that interaction between the activated B-cell and the TSH2 cell, which is why targeting B cells seems to be such an effective means of controlling the disease and why the B cells have been such a prominent target as a therapeutic target. Next slide. Making the diagnosis of IgG4-related disease is notoriously challenging. There is no single diagnostic test for IgG4-related disease, and there is no single specialist that is kind of routinely known to be the person to make the diagnosis. Many people think of serum IgG4 or IgG4 staining in tissue as the diagnostic test for IgG4-related disease, but unfortunately, both of those are nonspecific. They can be seen in other diseases, and particularly serum IgG4 can be normal in up to about 20% of patients with IgG4-related disease. So this is part of the reason that there is underdiagnosis is that particularly patients with normal serum IgG4 concentrations don't come to a diagnosis because people interpret a normal serum IgG4 as concrete evidence that they don't have IgG4-related disease, which is simply not true. So, as is the case with many other systemic autoimmune diseases, the diagnosis of IgG4-related disease really comes down to the clinician. The clinician needs to incorporate information from the patient's symptoms, the physical exam findings, the serologies with the serum IgG4 concentration and other lab abnormalities that are associated with the disease. What radiologic features are present? We typically get imaging of the chest abdomen and the pelvis in everyone that we're working up for IgG4-related disease because so much of it can be asymptomatic. And of course, whenever we can, we incorporate biopsy results or histopathology into the diagnostic process. And the most important elements of the diagnosis are, one, to identify the features that are consistent with the diagnosis, but just as importantly is to identify the features that are not consistent with the diagnosis because there is substantial overlap between the way IgG4-related disease presents and the way malignancies and infections and other autoimmune diseases present. So it's incredibly important for the clinician to recognize how complex the whole presentation can be. And that's part of the reason that it has been challenging to get many of the patients to the right diagnosis. So it is a challenge. But fortunately, I think there is increasing interest in not only the rheumatology community, but in the gastroenterology community and various other specialties. And I do think anecdotally that there's increasing awareness of this diagnostic process and that more people are working to get patients to the right diagnosis. Next slide. The burden of IgG4-related disease is quite substantial. I think we've talked a little bit about the clinical burden already. So patients with IgG4-related disease are at increased risk for mortality compared to matched controls in the general population. and they very often have more comorbidities like hypertension, other cardiovascular morbidities, diabetes, malignancy, and coronary artery disease. And we've certainly discussed the damage that can happen in the disease as a result of longstanding inflammation in organs, but there's additional damage that can happen because of the diagnostic and therapeutic process. It's very common for patients to have organ resections, including major abdominal surgeries to remove portions of the pancreas because of presumptive diagnoses of cancer prior to getting to the right diagnosis of IgG4 related disease. So earlier diagnosis has the potential to limit a really substantial amount of damage or the earlier diagnosis and, of course, treatment. There's also a significant treatment burden where over 85% of patients receive glucocorticoids as part of their treatment strategy, and there is a very well-documented and very well-recognized toxicity associated with glucocorticoids, something that many patients with IgG4-related disease end up burdened with, and it's probably more common for that to happen in IgG4-related disease and many other autoimmune diseases because it is a disease that tends to favor older adults. And because of the frequent endocrine insufficiency of the pancreas, these are patients who are already predisposed to getting diabetes, which is one of the most common toxicities associated with glucocorticoids. So these are patients that are really at high risk for treatment-related burden, and they really do experience that. And, of course, because of the relapse rate, where 30% relapses in six months, and if you extend that out to three years, it's about 90% of patients will relapse. So, these are patients who end up being exposed to a really significant amount of treatment, and they really need steroid-sparing options. There's data that show that IgG4-related disease impairs the quality of life patients and has a significant psychological effect as well. And we also have good data that shows that IgG4-related disease is associated with increased healthcare utilization, with increased use of emergency rooms and hospitalizations, as well as direct and indirect costs associated with the disease. Next slide. So, where we currently stand is we have a lot of unmet needs in IgG4-related the disease. I'm pleased to say that we've made great strides over the past two and a half decades since the disease was first recognized, but we still have a significant need for earlier recognition of the disease. We need better education among providers of various different specialties and among patients who might have manifestations of the disease and not know it because we need to reduce diagnostic delays and be able to initiate treatment before damage accrues. We need better diagnostic markers, again, to facilitate earlier and more accurate diagnosis. Serum IgG4 is currently the best biomarker that we have in the disease, which is pretty unacceptable considering 20 percent of patients will have a normal serum IgG4 concentration. We need longer-term data with prospective data, prospective studies and registries to understand to epidemiology on a deeper level, to understand the relationship between disease activity and organ damage, how much of the fibrosis that we see is reversible, and more patient-centered outcomes. And, of course, we need safer and more convenient therapies. We're very lucky to have therapies available to us, but as we'll discuss more over the next several slides, there is definitely an unmet need for having options that improve the safety profile and the convenience of the treatment. Next slide. And with that, we can now move on to discussing the INDIGO trial results themselves. So, this was a paper that was published in the New England Journal. And next slide, here are the disclosures associated with all of the authors on the INDIGO trial. Importantly, Obexilimab is investigational and has not been approved by any regulatory authority for the treatment of IgG4-related disease. Next slide. So, a bit of background before we talk about Obexilimab specifically. As we talked about, IgG4-related disease is a chronic progressive fibrin-inflammatory condition that can impact single or multiple organs and characterize their recurrent flares and lead to organ damage. Gucocorticoids are used as the initial therapy for rapid disease control in the majority of patients, but patients almost invariably relapse and or develop toxicity. Currently, the only FDA-approved approach for treating this disease is B-cell depletion, which is used for inducing and maintaining remission, but this approach has significant risks and limitations, both in convenience and in real-world applications. slide. And here are some of those risks that are important to talk about. And this is the reason that it's really important that we have more options, because the reality is B-cell depletion is remarkably effective in IgG4-related disease. We've known that for over a decade since the first large study of rituximab was published. However, there are significant downsides to be aware of with B-cell depletion, and these are things that I think rheumatologists in particular are very familiar with. So, the way B cell depletion works is after administration, B cells are depleted, meaning they're unmeasurable in blood, for around 6 to 12 months. It's very significantly from person to person. And during that time, it is irreversible, meaning that if a patient gets an infection or has a really significant need for a vaccine, like, for example, if there's a pandemic and we need the patient to be vaccinated, there's no way to bring those B cells back until they just come back on their own, and that can take a really long time. So, that's important to recognize. On top of that, with long-term continuous B cell depletion, meaning scheduled infusions every several months, typically every six months for most agents, And when that's done, it's very effective in controlling the disease. But over time, the longer someone is on B-cell decretion, it leads to progressive reduction in the total IgG, the total antibodies that we measure in the blood, which translates into, over time, it leads to cumulatively increasing risk of infection. So unlike many other immunosuppressive agents, where as long as someone is on it, they're immunosuppressed, but essentially to the same extent, with B cell depletion, the longer they're on it, the more it suppresses their immune system and the higher the risk of infection. And that's important in and of itself, but it's also important because occasionally those effects that it has on IgG are actually irreversible, and sometimes patients end up requiring lifelong replacement of immunoglobulins with IDIG, which is an added burden to patients, and that's also reduced the risk of infection. On the other hand, many of us treat with B-cell depletion using an on-demand approach where we treat for a short period of time, the disease goes into remission, and then we wait essentially for the disease to relapse before treating again with the intention of limiting the amount of cumulative exposure that the patient gets with respect to B-cell depletion. And the challenge with that is that it requires patients to have to go through relapses, which is challenging for quality of life and for the psychological effect of kind of waiting to have a relapse of their disease. And there's also the potential that by allowing patients to have multiple relapses, we're increasing the risk of damage over time. So, both the on-demand and the continuous approaches have really significant drawbacks there. And then, of course, B-cell depleting agents are also administered as intravenous infusions, which, you know, the patient has to come to the infusion center, spend several hours there. It's less convenient. And just in terms of logistics, that often leads to a pretty substantial delay in treatment because we have to coordinate with the infusion center and there has to be availability and with insurance coverage and everything. It's not uncommon for it to take two months or so between the time that we decide to treat with B-cell depletion and when they actually get the medication through the vein. Next slide. Which brings us to obexilimab and where obexilimab differs. So obexilimab is a humanized bi-functional monoclonal antibody, meaning that it's a single antibody that has two functions. It binds both to CD19, which is a marker on B cells, and it also binds to the FC gamma R2B receptor, which initiates an inhibitory signaling pathway. So the way this works is it targets the B cells, but rather than killing them, it does not induce cytotoxicity or or cell killing, rather than killing them, what it does is it inhibits them. It leads the B cells to stop functioning with the idea there that hopefully it would be less immunosuppressive, but also it would be reversible. And we do know that when Obexolimab is stopped, the B cells do kind of bounce back fairly quickly. And that's a major differentiator from Obexelmab and B-cell depletion. Next slide. Here's the study design of the INDIGO trial. This is a fairly standard and straightforward study. And it was the second global double-blind randomized placebo-controlled phase 3 trial conducted in IgG4-related disease and the largest one to date. The trial required all patients to fulfill ACR ULAR classification criteria and have active disease requiring treatment with glucocorticoids. During screening, they were treated with 20 to 60 milligrams of glucocorticoids. And then from day one, they were on 20 milligrams of prednisone that was tapered over eight weeks in a pre-specified taper that was the same for both Ovexilumab and placebo. Patients were randomized one-to-one to receive either Ovexilumab, 250 mg subcutaneous injections weekly, or placebo injections weekly. And they were followed in the randomized controlled period for 52 weeks, at which point they had the option to roll over to the open-label extension where they would receive Ovexilumab for up to three years. open label. Next slide. The endpoints of the INDIGO trial, the primary endpoint was timed to first IgG4 related disease flare requiring initiation of recipe therapy, and this needed to be in the opinion of the investigator and confirmed by a blinded adjudication committee. The key secondary endpoints were timed to first investigator determined flare requiring initiation of recipe therapy, which did not include the adjudication committee. The second was number of investigator and adjudication committee determined flares requiring initiation of rescue therapy. Third was the proportion of patients who achieved complete remission at week 52. And fourth was the cumulative dose of glucocorticoid rescue therapy through week 52. Next slide. Flares were assessed fairly systematically in this trial, so there were flare criteria that were developed specifically for this trial by an international panel of experts, and there were organ-specific definitions that allowed for detection of some subclinical and asymptomatic disease activity, which would count as flares in specific specific instances, depending on the organ involvement. The assessment of flares was comprehensive and included symptoms, physical exam findings, laboratory markers, imaging findings, and the criteria were tailored to every specific organ involved. At each visit, investigators evaluated patients for flared, and very importantly, this was the first trial to date that blinded investigators to serum IgG4 concentration, which I think was an important element of this trial design because we know that any treatment that targets B cells is going to have effects on the immunoglobulins, including IgG4. So it would be expected to see a reduction in IgG4 in patients who were being treated with the drug, and being blinded to that I think was really helpful in standardizing the assessments and making sure that flares were truly flares and not simply reflecting serum IgG4 concentrations. And all flair determinations, as I mentioned before, were reviewed through a blinded independent adjudication committee with a majority vote. And this approach was intended to ensure really consistent and rigorous assessment of disease activity across the study. Next slide. This is the largest clinical trial in IgG4-related disease to date. 194 patients were enrolled from 15 countries in North America, South America, Europe, and Asia. And you can see here that there was a really broad representation across the globe. Next slide. This is the trial disposition. This is what happens to the patients who were screened and enrolled. So, 287 patients were screened, of whom 194 were randomized to obexilinab or placebo, 97 patients in each arm, and just under 90% completed the 52-week follow-up period in each arm. Next slide. This demonstrates the baseline demographics of the patients enrolled in indigo, and this is fairly consistent with most of the literature that we have in this disease. There was an Asian predominance, which is not surprising considering there is a really strong representation of Asian investigators who are actively involved in this disease. The average age was just under 60, and there was a male predominance. These data are all quite consistent with the published literature with respect to IgG4-related disease. Next slide. And here are the clinical characteristics of the patients enrolled in the trial. So around two-thirds of patients had recurrent disease as opposed to newly diagnosed. And I would say that that's a higher percentage than the previous trial that was published that had a larger percentage of newly diagnosed patients. The vast majority of patients had multiple organs involved, with around 60 percent having between two and four organs involved. And consistent with what we know about the disease, the most commonly affected organs were the salivary glands, the lacrimal glands, the pancreas, and lymph nodes that are also very commonly involved. The disease duration at the time of enrollment was around two and a half to three years on average and 11 or 12 percent of patients had prior exposure to rituximab. Next slide. And here's the top line results. This is the primary endpoint and I think it's a very clearly positive trial as you can see from the Kaplan-Meier curve on the right of the screen. 73.2% of patients receiving obexilinib remained flare-free through the 52-week follow-up period. And the hazard ratio for flare was 0.443 with a 95% confidence interval ranging from 0.277 to 0.711. So this was a strongly positive result. All of the key secondary endpoints were also met. So, the time-to-first investigator-determined flare was 26.8% in the ovexilumab arm and almost double that in the placebo arm. The annualized rate of adjudicated flares requiring rescue therapy was, again, just about half in the ovexilumab compared to placebo. So patients achieving complete remission were also more frequent in the Bexelumab arm of 37% compared to around 20% in placebo arm. And very importantly, the glucocorticoid exposure was substantially different between the two And this is something that I would say rheumatologists in particular are really paying attention to because especially over the past five to 10 years, there has been really significant an interest in limiting glucocorticoids because of the really substantial toxicity that they're associated with. And we'll go over that in a little bit more on the next slide. Here's a little bit more about the glucocorticoid toxicity and the effects that ObexelMAP had on that. So the glucocorticoid toxicity index is a validated index that measures the amount of of glucocorticoid toxicity experienced by patients that looks at many different domains that are associated with glucocorticoid toxicity, ranging from body mass index, glucose tolerance, blood pressure, lipid metabolism, whether the patients had infections, or if they had really specific manifestations of toxicity like glucocorticoid myopathy, skin toxicity, or neuropsychiatric effects. And the component of the GTI, the glucocorticoid toxicity index, that's shown here is the cumulative worsening score, which the way this is designed is it's a cumulative score, so it can only increase over time, so you can't have a negative score with a cumulative worsening score. And here you can see that the placebo arm had substantially more glucocorticoid toxicity with respect to the cumulative worsening score, whether you look at a cutoff of 20 points or 30 points, that was seen. Next slide. This slide shows the effect of Opexilumab on serum IgG4 concentrations. As I mentioned before, serum IgG4 is probably our best biomarker for disease activity in this disease. And consistent with the overall top line results, we saw that CRMIDG4 concentrations were suppressed after the initial glucocorticoid taper that was done as part of the initial trial design. And those levels remained stable while the patients were on obexilmab. As opposed to the placebo armor, you can see that as soon as the glucocorticoids were discontinued, the CRMIDG4 concentrations began to rise again. Similarly, B-cells were reduced in both treatments. We know that glucocorticoids reduced the total burden of B-cells in blood and in tissue. And in the Obexolimab arm, the B-cells were lowered compared to placebo, but very importantly, they actually remained above the lower limit of normal. So, again, another kind of differentiator between B-cell inhibitions and B-cell depletion, where with B-cell depletion, we really expect the B-cells to be essentially undetectable as long as the drug is still in their system. Next slide. And here are the adverse events. I would say that this is quite reassuring. So, almost all patients had at least one adverse event in both the covexilumab and the placebo arm. but serious adverse events were numerically less common in the obexolimab arm, and grade three or more adverse events were also numerically less common, with 11% in the obexolimab arm and 24% in the placebo arm. Injection site reactions were a great grade two or above were uncommon, So, only 2% in the Obexelimab arm and 1% in the placebo arm. There were three malignancies in the Obexelimab arm and zero in the placebo arm, but all three malignancies were deemed unrelated by the investigator. Next slide. In conclusion, Obexelimab significantly reduced the risk of IgG4-related disease flare compared to placebo through week 52. There was reduced cumulative glucocorticoid rescue use, and it was associated with less glucocorticoid toxicity worsening compared to placebo. Obexilumab was generally well-tolerated with no new safety signals, and overall, Indigo demonstrated that B-cell inhibition through CD19-XC-Gamma-R2B co-engagement may present a novel subcutaneous treatment approach for the management of IgG4-related disease. This is the manuscript for Indigo that was published in the New England Journal of Medicine. And I'll hand it back to Lonnie to discuss the next part.

Leon O. Moulder, Jr., CEO

Thank you, Dr. Katz, for that comprehensive review. And we appreciate you staying with us for the upcoming Q&A session. I'll now hand the call over to Joe Farmer, our president and COO, who will take you through the IgG4RG opportunity and our commercial launch plans in detail.

Joseph L. Farmer, COO

Thank you, Lonnie. I want to start by framing the size of the opportunity in front of us and then walk through how we're preparing to capture it. Bonnie alluded to earlier, we estimate that the current diagnosed and treated population, IgG4RD, is about 25,000 patients in the U.S. Of that 25,000 approximately, we expect a payer mix of roughly 60% commercial, 30% Medicare Part D, and 10% Medicaid. Coverage requirements vary by insurance carriers, and we're preparing for those differences. For commercially insured patients, we're preparing to help physician offices navigate prior authorization and step therapy requirements. For Medicare Part D, we're building support for coverage exceptions and appeals. And for Medicaid, we're planning for differences in coverage requirements across states. Across all three, our focus remains the same, helping patients seamlessly onboard and access treatment, which will be discussed later. Taken together, as described earlier, assuming half of the currently diagnosed and managed patients are eligible for treatment and assuming the pricing of the FDA-approved therapy in this indication as a benchmark, we estimate that the IgG4RD represents a very substantial U.S. market opportunity approaching $4 billion. It's worth pausing on what we've already seen in this market. The first approved biologic in IgG4RD received FDA approval in April of 2025, and its launch trajectory is giving us a clear and encouraging signal about how this market is evolving. As of August, we estimate approximately 1,200 unique patients have been treated with the approved biologic prescribed by more than 950 unique physicians, a significant number of whom have prescribed more than once. The commercial infrastructure behind this drug has scaled accordingly, as we believe the field-based team supporting it has grown from approximately 35 at launch to over 50 today. The currently approved biologic is priced at approximately $150,000 gross per IV infusion, or $450,000 annually for new patients, and $300,000 annually thereafter, noting that new patients receive two infusions two weeks apart and then an additional infusion every six months thereafter for the approved label. What this all tells us is that the diagnosed IgG4RD patients are out there. Their treating physicians are amenable to biologic therapy, and this market is actively growing. This is exactly the environment we want to be launching into. Let's turn to the current treatment landscape and why we believe there's still a significant unmet need. IgG4RD is a progressive chronic disease that requires chronic therapy. That's the critical starting point. In a survey we conducted of 102 physicians, 94% agree that IgG4RD is a disease that requires proactive maintenance treatment. However, currently available therapies have significant limitations that may make sustained chronic treatment impractical and difficult. Most patients have received a glucocorticoid at some point in their disease journey because they're effective in treating flares. However, chronic steroid use comes with significant health issues and toxicity. Similarly, current B-cell targeting antibodies, which are depletors, one approved and one off label, have been utilized by a smaller percentage of patients, and while often effective, come with long-term risks and challenges, including increased risks of serious infection and an inability to receive necessary vaccinations. Older DMARs tend to be less effective, have toxicities, and therefore are used by an even smaller percentage of patients. Because the majority of patients are at a higher risk for toxicity, 40% are 65 or older, more than 30% have comorbidities and are at greater risk from infections, and 20% are less than 50 years old and facing decades of treatment. Therefore, B-cell depletion and chronic steroid use may not be well-suited for long-term disease management for these patients. We believe that what patients need and want is a convenient and effective therapy for chronic use. An agent that supports safe, long-term disease management without the tradeoffs of currently available therapies. That's the gap Ovexilumab is designed to fill, and it's a threat running through all we'll share with you today. To validate that belief, we went directly to the physicians who treat this disease and the patients who live with it every day. We surveyed 80 U.S. based IgG4RD treating physicians, with the majority of physicians being rheumatologists, immunologists, or gastroenterologists, hepatologists. Practice setting was well balanced between community and academic, and these physicians managed approximately 18 IgG4-RD patients on average over the past year, with more than 80% of those patients currently receiving drug therapy. We presented obexilmab to them, de-identified as product X, along with the Inigo study data, and asked about future expected prescribing patterns, assuming that product X was commercially available, and the results were quite compelling. The majority of physicians strongly agree that there's value in B-cell inhibition relative to depletion, with almost all of the remaining neither agreeing nor disagreeing, and we think the second group can be impacted for our education efforts. On the likelihood to prescribe, almost two-thirds told us they are extremely likely to prescribe ovexilinab, and when asked how they'd allocate their biologic use across ovexilinab and the approved and unapproved B-cell depletors, they assigned ovexilumab a 47% share, consistent with what we've seen in prior rounds of market research. In terms of when physicians would envision prescribing ovexilumab, the majority told us they'd use it first line or immediately following GCs or other immunosuppressants. And importantly, when asked what they do with the patient's flares while receiving ovexilumab, half said they'd continue the patient on ovexilumab and add GCs rather than switch therapies entirely. That's a strong signal of physician confidence in OPEXILMAP if approved once patients are established on it. A large percentage of physicians express the preference for weekly subcutaneous dosing over infusion every six months, with the majority not having a strong preference. This is not a market like you sometimes see in oncology, for example, where buy and bill may provide financial incentives that drive IV usage. Importantly, this data also shows that the physicians will defer to the preferences of their patients. To that point, in a separate, smaller study of 20 IgG4-RD patients, 75% said they prefer subcutaneous at-home administration with most of the remainder neutral. Although it's a small sample, it supports what we're hearing from physicians and patients that weekly sub-Q is preferred over IV treatment. With that research as our foundation, let me walk through how we're positioning OvexilNAV and where we believe it fits into the patient's journey. I believe ovexilumab offers a genuinely new approach to long-term disease management in IGG-4-RD, and that its unique profile positions it as the preferred first-line therapy for the majority of patients. The ovexilumab differentiation comes down to four key elements. First, long-term disease control without compromising safety. Second, the mechanism, inhibition, not depletion. Ovexilumab is designed to potently inhibit these cells through co-engagement of CD19 NFC gamma R2B, while, importantly, B cells not dropping below the lower limit of normal. That leads directly into the third element, reversibility. We expect that a vexilumab may provide physicians a real-world tool to pause therapy for a short period of time to assist in the management of infections or to administer vaccinations, something depleting therapies can't offer. We look forward to sharing additional data with you on the vaccination sub-study in the near future. Finally, at-home sub-q administration would eliminate the need for an infusion center, which, as our research just showed, is largely preferred by patients and providers. We plan to leverage these four elements of a vexilumab's drug profile to position it as the preferred first-line therapy for the majority of IgG4-RD patients. Our launch will target three patient groups, patients in active flare, patients considering a treatment change, and patients in ongoing chronic management. Patients in active flare would include newly diagnosed patients as well as previously diagnosed patients who aren't currently on therapy but are experiencing a new flare. Patients being actively treated include patients currently on an approved or unapproved biologic who see their physician prior to their six-month infusion and who the physician can then decide to switch based upon the Ovexil-NAP profile we just reviewed. So all of this comes together into three strategic imperatives for our launch. Our first imperative is to make proactive product disease management standard of care, shifting physician mindset away from simply treating players as they occur and building conviction that earlier, longer-term treatment is appropriate for more patients than are receiving it today. Second, differentiate clearly. We will make clear that inhibition as compared with depletion is an important clinically relevant distinction for physicians anchored in sustained disease control, reversibility, and patient safety. Third, execute with discipline. This means, among other things, build the conditions for fast, seamless uptake of a Vexil map for patients, providers, and payers. These strategic imperatives lead directly into our launch preparations, which include building the right customer engagement model. Our field model is built around targeted HCP, account concentration, and centers of excellence, along with understanding referral dynamics and community practice coverage. We're executing our engagement strategy accordingly to ensure we have all the key relationships and understand all these referral dynamics ahead of launch. We will also ensure that we prioritize the right customers. Rheumatology remains our primary specialty focus, with GIs also targeted at high-volume centers and referral networks. Let's now turn to how we're building out the commercial organization to execute against our strategic imperatives, starting with market access. We've built a coordinated cross-functional model designed to deliver comprehensive education and support at every HCP touchpoint. Our sales team, which will include 45 territory sales representatives plus five regional business directors, will deliver the necessary clinical and product resources to help physicians understand how and when to appropriately use Ovexilamab. Our market access team, including field reimbursement managers, will support HCPs and patients in navigating access and reimbursement, ensuring smooth patient onboarding, and working to minimize barriers between a prescription being written and a patient starting treatment. We also have a strategic engagement team who execute our commercial KOL strategy and build trust and relationships that inform how we go to market. We will also have a team of immunology nurse educators who will provide in-depth peer-to-peer disease state and treatment education to HCPs. Together, these teams create the surround sound that will provide HCPs with the education, access support, and trust the relationships they need to confidently bring a vexel mat to their patients. We've done the work to map the full patient access journey, and we've turned those learnings into core operating principles and a comprehensive patient support model. Critical to the success of the launch is ensuring that once a prescription is written, providers and patients have a seamless experience. experience, and we have developed a model that delivers on that. The model clearly defines responsibilities while delivering one coordinated patient experience. Once a patient is identified and a prescription is written, they either enter through our patient hub or directly to one of our two specialty pharmacies. From there, we handle benefits verification and prior authorization support and affordability triage, which will include quick start, bridge, co-pay, and patient assistance support programs. Obexilumab is then dispensed to the patient through our limited specialty pharmacy network. The goal is simple. Patients and providers should experience one Xenis model that allows the patient to seamlessly start and stay on therapy. To make this a bit more concrete, here's an illustrative pathway. Whether the prescription comes through our patient hub or directly through a specialty pharmacy, the model will support coverage, affordability, treatment initiation, and ongoing refills. We're also planning for where things can go wrong. Take a common scenario, missing coverage documentation causes a delay. In our model, an assigned owner identifies the missing information, and then the hub, specialty pharmacy, and our field reimbursement manager coordinate the response with the office, and the office and patient receive a clear next step that keeps the prescription moving forward, including potentially through one of the support programs that I mentioned a moment ago. We've selected our access partners with complementary strengths in mind. So patients and providers experience one coordinated Zenist model, no matter which partner they touch. RareMed will serve as our hub, managing co-pay support, our patient assistance program, Quick Start, Ridge, and free drug programs. For specialty pharmacy services, we've partnered with Biologics by McKesson for its scale and launch expertise, and or CME for its personalized rare disease-focused support. The expectation is that these partners work together as one Zenith support model that provides exceptional services for patients and providers. Let's now move to how we're deploying our field team in support of this opportunity. We've identified approximately 7,100 healthcare providers to prioritize at launch, organized into four tiers that correlate with known or presumed IgG4RD patient volume under their care. Biologic use and physician specialty helped to further refine and assist with the targeting to determine our field sales team deployment. It's important to note that the physicians within these four tiers account for over 70% of all currently treated IgG4RD patients, reinforcing the strength of our HCP targeting strategy. Having established our priority targeted HCPs, of which rheumatologists represent the largest number. We then moved to enhance our overall coverage by identifying the accounts, offices, or clinics where these patients are actually treated. This account-level focus allows us to effectively target and cover over 90% of all currently known IgG4RG patients, with the top 100 accounts representing 65% of the treated patient opportunity. This targeting effort, along with industry workload assumptions, resulted in the sizing of an optimal field force of 45 sales reps deployed across five regions to effectively cover the market. So, to bring it all together, we have an experienced team ready to execute a proven launch playbook, and we will be launch ready ahead of our May, Padufa, day. We believe we're very well positioned, appropriately resourced, and well-funded to capitalize on this very substantial opportunity for a VEXO or MAP in ITG4RD. With that, I'll hand it back to Lonnie for closing remarks.

Leon O. Moulder, Jr., CEO

Thank you, Joe. I hope today provided a clear picture of the unmet need in IgG4RD, the differentiated profile we believe of Bexlamab offers, and the discipline behind our launch preparations. We're excited about what's ahead, both for patients living with this disease and for Xenus, as we prepare to become a true commercial stage company. With that, we're happy to open the line for questions.

Operator

Operator? thank you we will now begin the question and answer session if you'd like to ask a question please press star one one if your question hasn't answered and you'd like to remove yourself from the queue press star one one again our first question comes from corey kasimov with evercore isi your line is open great uh good morning guys thank you for taking the question and thanks for hosting this event was very helpful um i guess i want to ask dr katz who appreciate you staying on for q a Okay.

Corey Kasimov, Analyst — Evercore ISI

What are the key factors that are going to drive your future treatment choices between Obexi and Uplizna? What would make you choose one product versus another for a particular patient? And when you put a patient on Obexi, how do you think about the potential treatment duration? I know this would be variable, but in a case where a patient's able to achieve low disease burden, how long might you keep a patient on therapy? Thank you.

Leon O. Moulder, Jr., CEO

Thanks, Corey. Dr. Katz.

Dr. Guy Katz, Analyst — Rheumatologist, Mass General Hospital

Dr. Yeah. Thank you for the question. So, there were two elements to that question. One is deciding between OBEXI and B-cell depletion, and the other is about duration of treatment with OBEXI. So, for the first portion of the question, I think the overall sense in the rheumatology world is that B-cell depleting agents are really phenomenal, and we know that in IgG4-related disease, they work just about 100 percent of the time, which is really nice to have an option that we know is going to work. But I mentioned earlier the downsides of B-cell depletion and why we worry about them, and in many other diseases, we really consider B-cell depletion to be one of the last results after we've exhausted other options. So I would think of Obexelimab as, in many patients with IgG4-related disease, a very appropriate first-line option for all of the reasons that we talked about in terms of the reversibility of it, the convenience, the fact that it's hopefully associated with a lower risk of infection. Of course, it's still too early to say that. We'll need longer-term data to say that with confidence, but I think the early data support that. And so in most patients, I see that as a good first-line option. The exception to that would be patients with potentially the most horribly severe disease patients in whom I'm worried any degree of active disease could be devastating. But the reality is that those patients are few and far between in IgG4-related the disease. Because it's such an indolent and slow disease, it is something that we generally have the benefit of time to try options to see what works. So I see this as being potentially first line for a large proportion of the patients that I see. As for the duration, that's another important differentiator between obexilimab and B-cell depletion. With B-cell depletion, I worry very much about the cumulative immunosuppressive risk of long-term B-cell depletion, but I don't think we have that same concern with obexilmab. So I see myself using obexilmab in most cases probably for at least, at the very, very least a year, but probably more like two or three years, depending on severity and prior relapse history and things like that. And then eventually trying to stop and see what happens to the disease. But I think many patients would end up sort of declaring themselves as patients who continue to relapse. And as long as they're doing well and tolerating the medication, I would kind of treat this the way that we do many other autoimmune diseases, where we continue it indefinitely and until such time that something changes in the patient's medical history that changes the risk benefit ratio of the treatment. So, I do see us using Ovexelumab long-term much more routinely than what we're doing with B-cell depletion. That's super helpful. Thank you.

Operator

Thank you. Our next question comes from Fiona Gia with Jeffries. Your line is open.

Fiona Gia, Analyst — Jefferies

Hi. Thank you for this very thorough presentation, and thanks for taking our questions. I have two, so for Dr. Taz maybe, what is the differential risk of prolonged B-cell depletion in IgG4, RD versus other diseases, for example, a lot of B-cell depleting agents were approved for RMS, which seems to be less of an issue, and just a quick follow-up, can you remind us when the vaccine data will be available and what are your expectations on the impact both on the regulatory perspective and commercial access.

Leon O. Moulder, Jr., CEO

Thanks, Fiona. Let me comment on the vaccine data. It is the initial data has been submitted, as we described in a recent news release. It will be present, as Dr. Katz well knows, as the lead author at the IgG4RD Symposium, coming up in a number of weeks and then also at the ACR meeting. And there is not a regulatory intent with that data set. That was your second part of that question, Fiona. But I'll turn it over to Dr. Katz for the first part of the question relative to B-cell depletion risk unique to IGG-4-RD?

Dr. Guy Katz, Analyst — Rheumatologist, Mass General Hospital

Yeah, so I think this is an important question as well. If I understand the question correctly, the question is about what are the effects of or the potential risks of long-term B-cell depletion in IGG-4-related disease as opposed to other diseases in particular. The challenge is because IgG4-related disease is a rare disease, and it's not until very recently that we started having large clinical trials in the disease, we have relatively little long-term data. And when we're talking about risks of B-cell depletion, we're talking about rare risks. So rare risks in a rare disease become much more difficult to study. So we have many open-label and observational studies of rituximab, and we have the MITIGATE trial of anabolizumab, and that's everything that we have in terms of the data on B-cell depletion and IDG4-related disease. And we don't have data in large numbers on patients who were treated for many, many years just because those data don't exist. So a lot of what we do is we extrapolate from other diseases, and we do know that that the risks of B-cell depletion have been shown time and time again in every disease where they're studied, and that includes things like rheumatoid arthritis and anti-associated vasculitis, where patients are very often treated with B-cell depletion for many years. And there is a very consistent effect that the longer someone is on B-cell depletion, the lower the IgG levels are, and the higher the risk of infection. This is kind of well-documented across several different diseases. And so that, I think, has been pretty consistently shown, certainly in rituximab, which is the oldest B-cell depletion agent that we have, so the one that we have the most data on. But the other B-cell depleting agents that have been introduced to the market have also shown a very similar trend where with long-term administration, at least the IgG levels go down. Not all studies have been able to show that that is associated with an increased risk of infection. But again, we just need really high sample sizes and follow-up times to be able to demonstrate that in a study, particularly of rare disease.

Fiona Gia, Analyst — Jefferies

It's very helpful. Thank you.

Operator

Thank you. Our next question comes from Yatin Sanue with Guggenheim. Your line is open.

Dr. Guy Katz, Analyst — Rheumatologist, Mass General Hospital

Hi, everyone. Thank you for the great presentation. Maybe just a couple of usage questions for me for Dr. Kaz. Dr. Kaz, could you maybe talk about your current practice and your usage of CD20 and CD19? You know, as you see newer patients, how are you prioritizing CD19 over CD20? And for patients who are on a CD20, who are stable, what is your plan? Are you going to switch them? And if you switch them, how should we think about a switch to a depleter versus an inhibitor?

Leon O. Moulder, Jr., CEO

Thanks, Yad. Dr. Ketz.

Dr. Guy Katz, Analyst — Rheumatologist, Mass General Hospital

Yeah, so I'm happy to share my practice. I think that there is some practice variability here. The way I see anti-CD19 and anti-CD20 agents is they're much more similar than they are There are some benefits of anti-CD19 compared to anti-CD20 in terms of convenience and differences in mechanism of action and things like that, but they are very similar, and both of them are remarkably effective in just about every patient with IgG4-related disease. For me, when the anti-CD19 monoclonal antibody became FDA-approved and was available, I started using that routinely for patients with newly diagnosed disease, and in patients who I had previously treated with rituximab, I would discuss the benefits and risks of both options with the patients and kind of leave it up to them, and some patients preferred to stick with what they already tried and knew worked in the past, and other patients preferred to try the newer agent because of the differences in how they work. So to me, the decision of B-cell depletion versus B-cell inhibition comes to individual patient factors. In a patient with virtually every organ in their body being inflamed, where I'm worried that something catastrophic is going to happen if I don't get them completely fully into remission yesterday, then those rare patients are patients that I would reach for B-cell depletion first before considering other options. But that is a small proportion of the overall patients that I see. And I have a referral bias with the patients that I see. I do see probably the most severe patients that are out there. I get referrals from all over the country and sometimes from other countries as well. So even in my particularly severe patient population, it is a minority of patients who are so severely ill when I meet them that I would, you know, jump straight to B-cell depletion before considering other options. Most other patients, I would feel comfortable trying Ovexolimab first because of its favorable safety profile and convenience. And in patients who have had prior flares after treatment with B-cell depletion and who have demonstrated that they kind of need ongoing treatment, those would be patients that I would be very interested in switching from the chronic management with B-cell depletion to Obexelimab with the intention that hopefully we'd still be able to keep them in remission, but would be associated with less of the cumulative risk of infection over time.

Operator

Thank you. Our next question comes from Judah Frommer with MS. Your line is open.

Judah Frommer, Analyst — Morgan Stanley

Thanks for the presentation today, and thanks for taking the questions. Maybe for Dr. Kess, just curious on your take for the convenience argument here. You know, do you have a sense for, you know, whether patients would prefer that weekly at-home kind of self-administration? And just maybe curious more from the company's perspective, I guess, how much are, you know, at-home administered injections like GLP-1s impacting, you know, the demand or maybe the receptivity for an administration amount like this?

Joseph L. Farmer, COO

Good morning, Judith.

Leon O. Moulder, Jr., CEO

Dr. Katch?

Dr. Guy Katz, Analyst — Rheumatologist, Mass General Hospital

Yeah, I'm happy to share my experience, which I will admit is more from other diseases than from IgG4-related disease, because up until, well, hopefully soon, I've had no subcutaneous options to offer my patients with IgG4-related disease. But I also see general rheumatology patients. I see a lot of patients with rheumatoid arthritis and psoriatic arthritis, and I'm often having the conversation of when someone needs to start a biologic, whether they prefer a subcutaneous or an infusion, and almost every patient prefers subcutaneous injections over infusions, at least initially. Rare patients prefer infusions because it's just kind of taken care of for them, but those patients are quite rare. So I think Joe talked about some of the market research that was done, and he may have some things to add there, but my anecdotal experience reflects that, that most patients would prefer to be on an at-home weekly subcutaneous injection rather than having to go in for infusion.

Leon O. Moulder, Jr., CEO

And that's consistent with not only the market research, but just all the conversations we have with our current investigators and key opinion leaders. And just as you said, Judah, perhaps GLP-1s were a major shift in how people think about delivering their own medications. But clearly in rheumatology, it's quite standard that at-home sub-Q is the preferred. Next question, operator?

Operator

Thank you. Our next question comes from Yigal Nakamovic with Citigroup. Your line is open.

Yatin Sanue, Analyst — Guggenheim

Hi, great. Thank you for taking the questions. I had a few for Dr. Katz as well, please. So the first one is, as you noted, the very severe patients are the small minority of the population. So I'm just curious, amongst your cohort, are there certain IgG4 patients where you're simply withholding the therapy given the potential for OBEX to be available, or is the current situation that everyone you see is either going to get rituximab or aplinza today? And then my second question, you know, you referenced the biomarkers and the 20% of the patients will have a normal IgG4 biomarker despite, you know, being classified as having the disease. I'm just curious if there's any new biomarker work that you're aware of that would, you know, maybe clarify that or make it more a better predictor. And then lastly, it was interesting that on the glucocorticoid talks, it's a very significant, obviously very significant three-fold decrease in glucocorticoid usage for the OBEX patients. But I noticed that the glucocorticoid toxicity index didn't fall by a factor of three. It fell more by, you know, a factor of, you know, 50 percent or something like that. I'm just curious if you could comment on the discrepancy there, please. Thank you.

Leon O. Moulder, Jr., CEO

Thanks, Yagol. I've noted the three questions, Dr. Katz, if you want me to go through those again, or jump right in?

Dr. Guy Katz, Analyst — Rheumatologist, Mass General Hospital

No, I'm happy to go through them. That's fine. Thank you, Lonnie.

Leon O. Moulder, Jr., CEO

Okay.

Dr. Guy Katz, Analyst — Rheumatologist, Mass General Hospital

So, I think the first question was about whether I would withhold treatment from patients who are currently active in anticipation of Ovexolimab becoming approved. If you ask me that question two or three weeks or even a month or two before I know that Ovexolimab is going to be commercially available, my answer may be different. Right now, I think it would be really unwise for myself or for anyone to withhold treatment from a patient with active IgG4-related disease because during the several months that it's going to be between now and when Ovexolimab will be approved, they could accumulate pretty significant organ damage even if they feel well. So patients who are active now I'm treating with B-cell depletion for the most part. But I've already started having conversations about ovexolimab with patients, and they've expressed some interest. There are patients that I anticipate potentially treating with B-cell depletion now and then after ovexolimab becomes available to have a conversation with them again then, but potentially started then either to treat a relapse or to prevent relapse at that point. So those are conversations I've already started having with patients, and I've spoken with other IDG4-related disease experts who've been doing the same thing. I think a lot of patients are really excited about the opportunity to have a weekly injection rather than an infusion, and one that has a potentially much better safety profile. So those are conversations that I've already started having with patients, But I don't think it would be right to withhold treatment from patients who have active disease this early on before Ovexil-MF is going to be commercially available. The second question was whether there are better biomarkers than serum IgG4 that are being explored. And yes, there are many researchers who are looking into biomarkers and trying to find better biomarkers. So far, we haven't found anything that works better than serum IgG4. but there's a lot of work that's going into it. There are some promising contenders. I just think it's all too early for prime time. I think we need some more data, some more longitudinal data, larger sample sizes, but there's a lot of work happening in that, and hopefully we'll have some more options in the near future. And then the last question, I hope I understood the question correctly, but it was about the glupal corticoid toxicity index, the GTI. And the question was why patients with the Ovexelumab also had an increase in the GTI. If I understood that correctly, I hope that's the case. The way that you...

Leon O. Moulder, Jr., CEO

Maybe I could clarify.

Yatin Sanue, Analyst — Guggenheim

Go ahead, you call. Oh, sure. Thanks. No, all I was sort of getting at was you had a very... In the OBEX patients, you had a, I think it was a, you know, three-fold decrease in the glucocorticoid dose, total dose delivered, but the glucocorticoid tox index didn't fall by that amount. It fell substantially, but, you know, not three-fold. It was, you know, less. I just was curious about that.

Dr. Guy Katz, Analyst — Rheumatologist, Mass General Hospital

I understand. Thank you for clarifying. I don't think that there's any literature to suggest that the changes in cumulative worsening score change linearly with the cumulative glucocorticoids that someone's exposed to. So I don't think that that's unexpected. And the way I think of glucocorticoids is the more someone gets, the more toxicity they get, but you can't ever predict exactly how much toxicity individual patient can get. Someone can be on 60 milligrams of prednisone for four months and have no problems whatsoever, whereas someone else can be on 20 milligrams of prednisone for two weeks and have avascular necrosis and diabetes. So there is a certain amount of unpredictability there, and I wouldn't really expect the cumulative worsening score to change linearly with the the amount of glucoborticoid exposure, if that makes sense. Yeah, okay.

Leon O. Moulder, Jr., CEO

The GTI data will be presented in a robust manner at the upcoming meetings I mentioned before, the IgG4 RG symposium in Boston and then also at ACR. And also, I mentioned previously that the vaccine sub-study data will be available. And we're, importantly, looking forward to the OLE, the overall 12-month flare probability, as another data set that will be available. So a number of things for people to look out for in the coming month or two. Next question. Thank you, Lonnie.

Operator

Thank you. Our next question comes from Matthew Caulfield with H.C. Wainwright & Company. Your line is open.

Dr. Guy Katz, Analyst — Rheumatologist, Mass General Hospital

Great. Good morning, guys. And thank you very much to Dr. Katz. So for Dr. Katz, does any of your experience with the PLISNA in the clinic provide insight into the possible ease of access for OBEXI? And if real-world pushback from payers could be cumbersome? Kind of just trying to get at any color on realistic access within the clinic. Thanks a lot.

Leon O. Moulder, Jr., CEO

Yeah, the access opportunity with PLISNA is strong. And, of course, Amgen's done a wonderful job of getting access, getting their product positioned. This isn't a disease that's managed to any substantial degree by payers. but I would ask Dr. Katz to comment if he's had some issues.

Dr. Guy Katz, Analyst — Rheumatologist, Mass General Hospital

Yeah, I will say my experience with getting an embolizumab approved has been remarkably positive. It is pretty uncommon for me to run into a situation where I can't get it approved for a patient who I want to treat them with it. There have been occasional payers now, some payers who were previously saying that rituximab is experimental and that we can't use it because there aren't any clinical trials that support its use. Now that we have an FDA approval for another medication that's more expensive than rituximab, some payers are requiring to fail rituximab before moving on to that. But that has been, at least for me, a pretty uncommon experience. The vast majority of patients that have prescribed uclizina were able to get it. And so, yeah, I've had a very positive experience with that in terms of how the insurance companies will respond to a second FDA-approved treatment. I think that's a little bit beyond my level of knowledge. Maybe Lonnie or Joe would be able to speak to that a little bit more.

Leon O. Moulder, Jr., CEO

Yeah, and just to comment, and Matt, you know this, everyone knows this, that the medical benefit is what covers rituximab and uplizna, whereas abeximab will be coming through the pharmacy benefit but one comment on a plizna the the last uh data we have in hand is just over 10 of all covered lives in the u.s require a step through of rituximab so that means nearly 90 do not and uh that's that's not surprising in an orphan disease and with a drug that has randomized phase three clinical data and again that would be the position we're in with

Operator

with the level of evidence and an FDA approval if approved and then of course as I said coming through the pharmacy benefit next question thank you our next question comes from Andy Chen with wolf research your line is open question for Dr. Katz, could you talk about the evolving trend of diagnosis and any dynamic for this disease that's making diagnosis go up?

Dr. Guy Katz, Analyst — Rheumatologist, Mass General Hospital

And maybe how quickly is the diagnosis growing and if you could provide a quantitative estimate? Dr. Katz, did you get that question? I'm sorry, I had a little bit of a hard time getting the question.

Leon O. Moulder, Jr., CEO

Thank you, Andy. It was related to the trajectory in increasing diagnosis of the disease, what you're seeing there?

Dr. Guy Katz, Analyst — Rheumatologist, Mass General Hospital

Yeah, so this has been at least to me fairly positive and I think is related to the fact that we now have phase 3 randomized controlled trials that are being published on this disease, so more people are paying attention to it. I think there's more talks that I'm seeing and being a part of at conferences like the American College of Rheumatology and ULAR. So I think there's increasing just kind of general interest in IgG4-related disease, at least in the rheumatology community, and I think in other specialties as well from what I'm gathering. I mean, I've spoken with various specialists in different areas, and I think there's just more and more interest in IgG4-related disease in general. And with that comes more education. So I think more people are able to recognize the manifestations of the disease, do the appropriate workup, and get to the right diagnosis. I do think our volume of referrals has been increasing over time pretty consistently over the past several years. And I think also a lot of people are managing patients without referring them to specialty centers like MGH. So, my anecdotal experience and I think the literature will support that there is increasing awareness and diagnosis of the disease. Awesome.

Leon O. Moulder, Jr., CEO

Thank you, Dr. Katz. I really do appreciate your participation today and all of you who joined the call. We look forward to speaking with you at our upcoming R&D Investor event and have a good This concludes the program.

Operator

You may now disconnect. Thank you.