Annexon, Inc. (ANNX) Earnings Call Transcript & Summary

Welcome to Annexon Biosciences 2024 R&D Day. [Operator Instructions] As a reminder, this call is being recorded today, March 1, 2024, and a replay will be made available on the Annexon website following the event. I will now turn the call over to Douglas Love, President and CEO of Annexon. Please go ahead.

Thank you, Sara. Good morning, everyone, and welcome to Annexon's 2024 R&D Day on Guillain-Barré Syndrome or GBS. We are excited to host the first ever R&D day on GBS, where we will focus on its serious unmet need and Annexon's novel therapeutic approach to tackling it. This morning, you will hear from Annexon management as well as from experts in GBS, who will provide both a patient and clinical perspective. We will be making forward-looking statements this morning, and our legal disclosures are indicated here. I'll start with a brief overview of Annexon and our work in GBS. We will then hear from Lisa Butler, Executive Director of the GBS/CIDP Foundation International, who will provide the patient perspective on GBS and the profile impact of this disease on people's lives. Dr. Hugh Willison, Professor Emeritus of Neurology at the University of Glasgow in Scotland, a recognized expert in autoimmune neuropathy, will then discuss disease pathophysiology, Annexon's anti-C1q approach and our clinical data generated today. Thereafter, Dr. David Cornblath, Professor Emeritus of Neurology at Johns Hopkins University School of Medicine and recognized expert in inflammatory neuropathies, will review Annexon's Phase III program with ANX005 in GBS. Finally, Michael Overdorf, Annexon's Chief Business Officer, will discuss the significant market opportunity in GBS and Annexon's commercial approach thereto. I will then provide brief closing remarks and open the line for questions. This is an important and exciting time with Annexon, where as you will hear this morning, we have made significant progress with our promising GBS pivotal program. Annexon was launched 10 years ago with a bold mission of frame the body, brain and eye of neuro-inflammatory diseases driven by aberrant classical complement activation. We have since remained sharply focused on stopping classical complement's aggressive inflammatory activity where it starts by blocking C1q, initiator of the pathway, to provide the most complete protection against its harmful activity and provide potentially unique functional outcomes as a result. Our first-in-kind wholly-owned pipeline is made up of multiple drug candidates with the potential to help millions of patients and their families suffering from devastating complement-mediated diseases. With consistent and promising progress over the last decade, we are now a late-stage clinical platform company poised to generate significant benefit for patients and shareholders in the near to midterm. Today, we are focused on our GBS registrational program, where we anticipate Phase III data in the second quarter of this year. This will be the first placebo-controlled data set in GBS in approximately 40 years, and it is supported by a robust proof-of-concept data and a well-informed and executed Phase III trial. Our classical complement pipeline also contains additional strategic priorities, including our potentially best-in-class registrational program in geographic atrophy, which is designed to provide protection against loss of vision in elderly vulnerable patients as well as our first-in-class oral drug candidate, ANX1502 designed to treat a host of devastating antibody-mediated autoimmune conditions with appeal. Importantly, we are well capitalized in to mid-2026 with runway through multiple mid- and late-stage clinical catalysts. Annexon is the only company with a classical complement pipeline targeting diseases of the body, the brain, and the eye. And collectively, our pipeline has the potential to treat over 8 million patients worldwide. With our universal focus on stopping harmful classical complement inflammation where it starts, we have developed diverse drug candidates across several indications, many of which have been clinically derisked and for which there are multiple upcoming late-stage and mid-stage clinical milestones. GBS is our most advanced clinical program where we have spent 10 years studying the disease, our mechanism of action and the patient population with the aim of transforming the treatment landscape for this devastating condition. In so doing, we have fostered important relationships with GBS experts across the globe, including with IGOS, a 2,000-patient prospective registry, that has greatly informed our understanding of the disease and our clinical approach. We have also conducted now 3 separate clinical trials in GBS, including both monotherapy and combination studies. And so as we sit here this morning, Annexon has established a deep-rooted history and commitment to treating GBS, which we believe enhances our overall likelihood of success to help patients get better sooner and more completely. All of that leads to now where Annexon is actively pursuing a monotherapy label in GBS. We're encouraged by the outlook and increasing external recognition of the program, having been granted FDA Fast Track and Orphan Drug designations, as well as EMA orphan drug designation based on findings of ANX005 potential for significant clinical benefit over the current standard of care. Our robust placebo-controlled Phase III trial in GBS has completed enrollment, and we look forward to reporting top line data again in the second quarter of this year. We thereafter anticipate submitting for a BLA with real-world evidence comparability data in 2025. With that overview, it is my great pleasure to turn the call over to Lisa Butler, Executive Director of the GBS/CIDP Foundation. Lisa, please proceed.

Thanks so much. I am Lisa Butler. I'm the Executive Director of the GBS/CIDP Foundation, where I have been for the past 10 years. So I'm going to begin by sharing my personal story and tell you a little bit about my son, Stuart, who had Guillain-Barré when he was just 5 years old. Here he is in his wheelchair and then they're saying thank you at the end of this journey. So at age 5, Stuart suffered from common -- what we thought was a common intestinal virus and he recovered. But exactly 4 weeks later, his Guillain-Barré journey began. At the time, he was a winning swimmer and winning all of his age group races. He was playing soccer, he was scoring goals. He was very coordinated, very active. He came home from school on a Thursday and said that his legs hurt and was complaining. We took him to the doctor and they suggested some x-rays. We had x-rays, nothing happened. By the next day, he started stumbling and we thought it was maybe being a little bit of a goofy 5-year-old. And then the stumbling turned into standing up and collapsing. And then he had kind of an awkward gait and was walking very wobbly. And by then, we thought something was really wrong. Back to the pediatrician where we saw that he could really only walk down the hall at the office by leaning up against the wall, so something was clearly happening. The doctor then saw the same thing and sent us to the hospital. Various tests were run. He had no reflexes. He was very, very weak. And they did what's called a lumbar puncture and tested the protein levels in his spinal fluid, which were elevated and very quickly, a diagnosis that Guillain-Barré Syndrome was made and Stuart was sent immediately to the ICU. By this time, only a day later after he had been admitted, he couldn't use his arms above his -- he couldn't raise his arms above his head. We were told that whatever was happening to him with his Guillain-Barré could eventually affect his lungs. He could need the help of a respirator to breathe. We were terrified. We were confused. What was happening? We were just watching our little boy wither away and lose strength of his body. Eventually, he lost use of his arms and his hands. We fed him. We took care of his daily needs, again, all in ICU as respiratory therapists came in hourly to see how his lungs were functioning. The doctors told us that Stuart was going to be treated with something called IVIG, which is an intravenous immunoglobulin, and that is made from human-donated plasma. Again, a little scary to us. We've never heard of this. We had no idea what it was. But in fact, it did begin to do its job. Stuart began to recover enough that he could be released from the hospital 2 weeks later, strapped to a wheelchair because he lacks the strength to even sit up on his own. We started PT and OT. We did speech therapy. We did aqua therapy, which he loved having been a swimmer, but his improvement really stalled, and he was still very, very incapacitated. We went back to the doctor. More tests were run, trying to measure this signal between his muscles and his nerves and the doctors are going to tell you more about that in a few minutes. And in fact, there was some delay in those signals and lack of signals, and this thing called Guillain-Barré was talked about with some permanent damage and that this could even be a chronic condition for our little boy. What was this future going to look like? We kind of gave up our thoughts of swimming or soccer or anything like that. All we wanted was our little boy to be able to walk on his own independently. So he was sent back to the ICU for another 5 days of IVIG. And in fact, then he did begin to recover. He came home, again, lacking all strength. He was able to lay on a square scooter board and kind of just flopped around the first floor of our house, and that's how he moved. We had a 3-year-old that did the same thing and a 6-month-old and a baby walker, so I had 3 boys on wheels. He eventually did begin to recover. At one point, leg braces were considered. And we wondered if our son was going to be a modern-day Forrest Gump for the rest of his life. It was a really, really scary, scary time. But eventually, after the second round of treatments, Stuart did begin to improve and did recover. So just to give you a recap of these dates. He was first admitted to the hospital and diagnosed on January 28. He was readmitted to the hospital on February 28. He took his first steps on April 20. And by May 30, he was released from therapy. He was so fatigued during this time that he began napping. And again, he was 5.5. 5.5-year-olds are not napping every day. He napped every single day. He was absolutely exhausted from this experience. By this summer, he was able to start playing soccer again but he was very, very slow off the line, did not have to get up and go and his legs that the other children had. My husband went to the GBS/CIDP Foundation symposium in search of answers. What kind of recovery was he going to have? Was it going to be complete? My husband came home from the conference, and I was so excited to hear the answers to our questions. And he said, "No, I walked in that room and I did not ask one question because all I saw was 500 patients and a mix of wheelchairs, walkers, assisted devices, canes, scooters." And my husband said, he kind of went from feeling fearful to feeling fortunate. But still, would he have a complete recovery? So again, this was the fall, and I'm very proud to say that by the winter, Stuart really did have a full recovery. So again, a 5.5-year-old child, he missed 3 months of school. This can happen to anyone, any age, anywhere, race, gender. The next slide, please. Here he is at age 27, recently engaged and showing off some of his water skiing skills. Next slide, please. So I want to share with you some adult patient comments. I went to the ER. I was turned away for fatigue, dehydration and stress. The next day, I could not stand. Legs buckled. Back to the ER unable to move my entire body, put on a respirator that same day. They told me they would give something called IVIG to help stop this, but I had no idea what that was. I did PT, OT, speech. I eventually stood up with assistance after 8 weeks. I took my first independent steps after 16 weeks. I was terrified. There was so much chaos around me as I was put in the ICU and told my body was paralyzed by this disease I had never heard of, and that I would likely require a respirator to help me breathe. I've learned that I was put in a medically-induced coma. They said I would recover to a new normal, but what was that? At one point, I can only communicate by blinking my eyes. I had so many questions that I couldn't ask. And we just, this week, heard from a patient that was celebrating his first day back at work after GBS. Eight months and 27 days, his first day back at work. Next slide, please. So how am I able to share all this with you? I'm going to tell you just a little bit about our foundation and the work that we do. We were founded in 1980 with our founder in her living room in Philadelphia. Fast forward to 2024, we now have 30,000 patients in our database, a 20-member global medical advisory board. You're going to hear from 2 of them. We have 57 global centers of excellence, 200 volunteers and 18 full-time employees. And we have always existed so that no patient would take this journey alone. Next slide, please. So we provide for this community by responding to over 100 patient questions a month. Here are some of the activities we do, but I want you to know that in 2023, we had 108,000 visitors to the Guillain-Barré page on our website, 676,000 overall visitors to this site, so a very, very active community. And we have a very, very incredible global medical advisory board. Next slide, please. So these are our global neuromuscular experts who lend their expertise and their time. They do consultations. You can see the various countries that they represent. And they have guided our Center of Excellence program, 28 in the U.S. and 22 globally. Next slide, please. We engage in research. We also work with the IGOS program that was mentioned earlier. We recently are supporting IGOS to create a GBS hub for the global health network, which provides assistance in developing countries, very, very important. We ourselves fund independent research, we fund consortium-based research. And we also have met with the National Institutes of Health for a State of the Science Meeting, again trying to keep GBS top of mind. Next slide, please. We work with the regulatory agencies as well. The Department of Defense has a peer-reviewed medical program. It's over $300 million in funding dedicated to about 40 conditions specifically and Guillain-Barré is one of those. They funded about $6 million so far. We had a what's called a patient listening session in 2019, with the FDA to inform them about this patient journey, and we're about to be hosting a patient-focused drug development meeting with the FDA so that they can hear from the patients, they can hear the unmet needs and understand this patient journey when they're presented with future innovations. Next slide, please. So our community has adopted the turtle and because the turtle's slow and steady progress. And they've taken the 3 letters, GBS, and they often talk about the fact that GBS in their minds means Getting Better Slowly. But what if we could change their future and what if getting better slowly became getting better sooner. These patients need and deserve new treatments, better treatments and they need to get better sooner. Next slide, please. It is my honor to introduce Dr. Hugh Willison, Professor Emeritus of Neurology at the University of Glasgow, Scotland. Dr. Willison?

Thank you very much, Lisa, for that presentation. Firstly, can I just say how delighted I am to see that Stuart recovered so well? And welcome everybody to the next section of today's presentation. I've spent my entire academic life working on clinical and basic aspects of Guillain-Barré Syndrome, and as a long-standing neurologist have also been involved in clinical trials and in the care of hundreds of patients with Guillain-Barré Syndrome. In the next 15 minutes, my presentation is going to cover the key features of GBS and the approach that Annexon have taken to develop their novel treatment with early classical pathway inhibition. Next slide, please. First of all, a few straightforward things about Guillain-Barré Syndrome. GBS has really replaced polio as the commonest cause of acute paralytic disease affecting the peripheral nervous system. It's caused by an autoimmune response triggered by a wide variety of infections that lead to nerve destruction and electrical impulse failure. The aberrant acute immune response to infection is the neurotoxic factor, comprising an acute phase anti-nerve autoantibody response that decays quite rapidly over time, explaining the self-limiting nature of the disease in most cases. Globally, there are around 150,000 cases of Guillain-Barré Syndrome per annum, and this translates into a lifetime likelihood of anyone developing the disease of about 1 in 1,000. The syndrome, as you've heard, is clinically manifested by severe muscle paralysis often requiring mechanical ventilation, without which death would be inevitable. In severe cases, mortality is still significant despite best medical care and recovery is often incomplete. Treatment with immunoglobulin, the current standard of care is only partially effective. It's slow to deliver. It's mechanistically obscure and has not changed in over 30 years. When benchmarked against diseases like multiple sclerosis, it's clearly time for the development and introduction of targeted immunotherapies. Next slide, please. We can think of Guillain-Barré Syndrome as having 3 phases: the acute paralytic phase in which the autoimmune attack on nerves is active. This is a self-limiting period to nadir from onset to nadir lasting around a week from symptomatic onset, in most cases, but may rarely last for 2 weeks or more. And as you heard from Lisa a few minutes ago, in some cases, it can last for longer than that or turn into a chronic condition. This acute early phase is the optimal anti-inflammatory treatment period, after which treatment is unlikely to be effective in most cases. Just like thrombolysis for stroke, missing this critical early treatment window is likely to result in treatment failure or, at best, attenuation of its effectiveness. The acute phase is then followed by a plateau phase of ongoing nerve failure due to tissue injury. And lastly, the recovery phase of tissue repair, which extends over a year or more. The next slide, please. Mechanistically, current evidence points towards aggressive autoantibody binding to nerve components with complement fixation through classical pathway activation. Autoantibody production is triggered by infections through a process termed molecular mimicry, in which the antigens on the microbial and nerve surfaces are structurally identical and therefore generate this autoantibody response. Both nerves, both peripheral nerve myelin, that's the insulating sheath that wraps the axon and the axon itself are targeted, and this varies an extent between geographical regions and between individuals. This knowledge has led to the classification of Guillain-Barré Syndrome into predominantly demyelinating axonal and mixed forms of the disease. If you move to the right-hand panel, you can see that the release of intracranial components including the neurofilament protein, neurofilament light into the circulation provides a key opportunity to use this as a biomarker for the severity and extent of nerve injury. And it is clear that there are significant and measurable axonal injury in all forms of the disease, including the demyelinating and axonal variance compared with healthy controls. The next slide, please. The evidence that complement is activated on axons and/or myelin comes from a variety of sources, including detailed pathological studies in humans and in experimental animals, in which the disease can be modeled. Here, we can see in human autopsy studies and in the cartoon on the right, the key steps of autoantibody deposition with complement fixation at the noble gap and on the myelin sheath and concomitant macrophage recruitment into the sites of injury. Next slide, please. Since autoantibody-mediated complement activation is a key step, complete and early inhibition of the classical pathway through C1q inactivation appears in principle to be an excellent therapeutic strategy based on the clinical and preclinical evidence that we have. Next slide, please. Through substantial international collaborative efforts and platforms such as the IGOS platform, the International Guillain-Barré Outcome Study, which Lisa has mentioned, and David Cornblath is going to mention a bit later, a range of prognostic factors have been identified as predictors of functional outcome as listed here. These include rating scales and scores, demographic factors, fluid biomarkers, and electrophysiological measurements. Next slide, please. With this background in mind, what might we, as clinicians and prescribers, wish to see in a novel GBS therapy? A first-line rapid onset, complement-targeted immunotherapy that was effective and safe in all GBS patients. Next slide, please. To this end, the Annexon team designed and then, in 2020, conducted an 8-week Phase Ib safety and tolerability study of ANX005 in a group of GBS patients and during the data analysis also identified several indicators of beneficial effects, which I'll run through now. Next slide, please. Firstly, the dose-ranging component of the study showed that there's an 18 milligrams per kilogram and above dose, C1q was rapidly and completely neutralized by ANX005 to 3 weeks in serum and also in cerebrospinal fluid. The latter finding is significant to CSF-based nerve roots in the subarachnoid space, the nerve routes being a key region of vulnerability to injury in GBS, indicating target engagement at this critical site as well as in the plasma. Next slide, please. Secondly, it was clear that ANX005 maintained its full anti-C1q effect in the presence of therapeutic IVIG, intravenous immunoglobulin, the latter of which had no appreciable effect on acute plasma complement inhibition in its own right. New paragraph -- sorry, next slide. In terms of the preliminary indicators of disease outcome that were discernible from this Phase Ib study, bearing in mind that it was principally a safety and tolerability study, the Annexon team looked at the patient group in whom full C1q inhibition was achieved, i.e., those that received greater than 80 milligrams per kilogram of drug, and compared them with placebo controls. Firstly, one brutal finding was that a significant reduction in neurofilament release from damaged axons into the circulation early in the course of the disease was observed for ANX005 compared with controls. Next slide, please. Secondly, muscle strength in the limbs measured through the MRC SOM score was significantly improved at several early time points in the disease course in the treatment group compared to the placebo group. Next slide, please. Thirdly, significant improvements on the GBS disability scale of the widely-used standardized disability scale at week 8 were observed in the ANX005-treated group relative to the placebo group, and this is also shown here in the form of a Grotta Bar. Next slide, please. So summarizing this Phase Ib study, several independent and distinct parameters comprising quantitative readings of neural damage, muscle strength and disability all improved with ANX005 compared to placebo. On the basis of these data, in October 2023, the EMA, European Medicines Agency, awarded Orphan Drug Designation to 005 use in GBS. One of the key points that the EMA raised was the potential for ANX005 in establishing significant benefit over approved standard of care. Next slide, please. So I think it's fair to say that in summary, Annexon has demonstrated in their Phase Ib trial that ANX005 has the potential to be of clinical benefit to patients with GBS by virtue of its immune targeting to a key specific pathophysiological pathway. Its very rapid onset of action. Its general applicability to all forms of GBS and a good safety profile. And I'll now pass you over to my colleague, Dr. David Cornblath and take any further questions later. Thank you.

Thank you, Professor Willison for that excellent talk on GBS, including the mechanism of action of ANX005, its relevance to GBS and the positive Phase Ib data. My name is David Cornblath. Like Professor Willison, I've spent a significant proportion of my academic career in Guillain-Barré Syndrome, from my first introduction as resident to the North American trial to the recent CGBS trial and the IGOS Group. I'll bring that to the next few slides. Next slide, please. With the Phase I data in hand and the knowledge of our GBS trials, Annexon then developed the Phase III trial with input from leading GBS experts from around the world. In my view, the unique features of this trial include: the shortening the time from disease onset to entry and importantly, then to study drug administration; the use of statistical methods to maximize the probability of the successful outcome; and using excellent sites with well, deep GBS experience who could successfully and rapidly recruit patients. Next slide, please. The Phase III pivotal trial critically shortened time to entry to increase the likelihood that their drug would work during the active phase of the disease, as Professor Willison has shown you. They have used the universally accepted GBS-DS score shown here both for entry using grades 3 through 5 and is the primary outcome measure at week 8. Randomization was 1:1:1 to high-dose ANX005, low-dose ANX005 or placebo following FDA advice. Standard secondary endpoints, all of which should moved in the same direction as the patient improves were included. These will all be measured at multiple time points for the first 6 months of the trial. Final trial data, as Doug has mentioned, will be available in the second quarter of this year. Next slide, please. For the analysis, the 7-step GBS disability scale has been collapsed into 3 more easily understandable categories. This allows for a more efficient statistical approach using the proportional odds approach. Under the proportional odds, Annexon will look for an improvement in the entire population's health status. That is a shift to the left, as shown in this Grotta Bar. Annexon and its experts will consider a win in this trial as a twofold shift to better on the disability scale versus placebo at week 8. Next slide. As mentioned, the important secondary outcomes assessing strength, disability, morbidity, and mortality will be assessed at multiple endpoints during the 6-month trial to support the primary outcome. In previous trials, these secondary outcomes, as I mentioned, move along and should be clearly supportive of the primary. Next slide, please. I've attended many of the FDA meetings with Annexon. I don't know whether that's good or bad. Anyway, FDA agreed that a single pivotal study is done by Annexon even though outside the United States, would be sufficient with a BLA, assuming it demonstrates 2 important features. First, of course, is substantial evidence of ANX005's treatment effect versus placebo in the GBS populations being studied. Second is the demonstration of comparability between the Phase III population in Western patients. Annexon has engaged with those of us in IGOS. As you've heard a prospective collection of real-world data from 2,000 GBS patients worldwide led by Professor Bart Jacobs at Erasmus Medical Center in Rotterdam, and with a group of external statisticians with extensive experience and comparability studies led by Professor Stiberg at Leiden University, also in Holland. This group, which I'm pleased to co-chair has initiated a real-world evidence comparability protocol entitled ANX005-GBS-04 in support of the BLA submission. Results from this study will be available in the first half of 2025. Thank you for your attention. I will now turn this over to Michael Overdorf, Annexon's Chief Business Officer.

Thank you, Dr. Cornblath. As Annexon, we are very excited about the opportunity to potentially bring a new treatment to patients who have been waiting decades for something new. And as Lisa said, these patients deserve more. And as a company, we are excited that as we prepare for what could be our first commercial launch as a company, and this is a moment that we've been working a decade for. Next slide, please. I want to start by just summarizing some of the key points that I'll be sharing in terms of the market opportunity and our commercial approach. First, we view this as a blockbuster commercial opportunity and we're preparing for it as such. I'm going to be sharing some increased GBS incidence numbers that show the full magnitude of this disease. Currently, there are no approved drugs in the U.S., and there's a significant disease burden despite available treatments, and we are going to target 005 as a first-line monotherapy single-infusion treatment for GBS patients. There's unique commercial dynamics associated with this. You have to view it different than you do other rare diseases. There are far fewer referrals in this disease, and it's driven by the indiscriminate nature, the urgent nature of the disease and the confidence that physicians have in diagnosing this. But GBS patients are geographically concentrated based on population, and that concentration allows us to have a focused commercial launch. We're going to be targeting hospitals across 3 different waves, and we're going to be using a focused commercial team of 3 primary roles of key account managers, medical liaisons and customer support reps. And then from a value-based perspective, GBS results in significant cost burden on patients, their caregivers, hospitals, and payers. And we see 005 as having the opportunity to provide value-based benefits and actually reduce the cost of care for these patients. Next slide. So in terms of incidence numbers, since there hasn't been a new treatment available in decades, it's spotty the incidence numbers. We see large ranges of what this could be on an annual basis. And so we wanted to get at what could be the true incident number. And so we just completed what we believe is the first-ever analysis of medical claims data in the U.S. And in fact, with our market research partner, 81QD, we took a look at 7 years' worth of medical claims data in the U.S. using the DRG code for GBS and then applying appropriate filters to make sure that we're getting at the true GBS patients, taking a look at them both while they are in the hospital and after discharge as well. And what we found through that assessment is the incidence rate in the U.S. is actually higher. It's 7,000. And these are actually 7,000 patients who are hospitalized and treated. Previous numbers that have been used are about 6,000 in the U.S., but that includes the entire population. That's what was assumed. And it's important to note that the 7,000 is conservative because it doesn't include those patients who were not hospitalized. And that could be 5%, 10% or maybe more of mild patients who were never hospitalized. They're not included in these numbers so these are, again, the 7,000 patients. Now in terms of Europe, clearly, we can't use claims data to get at those numbers, but what we did was talk to a number of physicians and hospitals in Europe across a number of countries, shared our methodology, understood their patient flow, shared different patient numbers. And what we determined is really the incident rate is the same across Europe. The incident rate is going to be the same between the U.S. and Europe. And given the population size of Europe, we arrived at a number of 15,000 of that annual incident rate for all of Europe rather than the 6,000 that's been used only for then in 5 countries. So if I can, I want to give a couple of areas of guidance as you think about building market models for this disease. First, we would encourage you to use these numbers. We've got a lot of confidence in these numbers. Second, again, these are the hospitalized and treated patients. So oftentimes, you'll take a population and discount that to get at what is available to be treated. These are the patients who are available for 005 or for IVIG. And then finally, adherence. This is a different dynamic. This is a single infusion, so adherence is 100%. So there's no reason to put any discount in models. Next slide. So there are unique commercial dynamics associated with this disease. First of all, it's an indiscriminate disease. GBS doesn't care. GBS doesn't care about your age, your sex, your race. It could strike anyone at any time. And as you've heard, there's an urgency to treat these patients, often experiencing paralysis, maybe difficulty in breathing. These patients are going to go to the hospital where their symptoms are presenting. They're not waiting to see a specialist a couple of months down the road or whatever. They are in an emergency condition. And you think about this as stroke. There's an urgency to treat. Time is important. The clock is ticking at that moment in time. And given that urgency to treat, physicians have confidence actually in diagnosing these patients, and it leads to lower referrals as compared to other rare diseases. Now while the referral rates are lower, the concentration of these patients is actually quite high. Next slide, please. And so we see that concentration in terms of these patients are concentrated based on the population. Where people are is where the GBS is going to be. And from our U.S. claims analysis on the left, we see where the GBS patients are and where they are concentrated, and this is consistent over that 7-year period. So we've got a very good handle on where the hospitals are who are treating these patients. And you can see where the patients are in comparison to the national population, and it lines up perfectly in terms of this concentration. And this concentration then allows us to have a focused launch. Next slide, please. And so that focused launch that we'll have will be targeting hospitals in 3 different waves. The first is going after the large metropolitan and academic hospitals, around 60 of those hospitals, who are treating the majority of GBS patients in the U.S. And in fact, the top 15 hospitals are seeing 15% of all the GBS patients. We'll then have a second wave where we'll target the large community hospitals, leveraging the experience and the endorsement from the wave 1 hospitals. And across wave 1 and wave 2, we'll be targeting roughly 75% to 80% of the hospitals who are treating GBS patients. And then finally in wave 3, we'll broaden out to the midsized community hospitals, primarily leveraging digital and peer-to-peer platforms. So this focused targeted approach to hospitals allows us to have a very focused commercial team and commercial footprint. Next slide, please. And that commercial footprint will be spread across 3 primary roles, key account managers, medical science liaisons, and customer support reps. The key account managers, they're going to have these higher-level, system-level interactions with hospitals, with P&T committees with the prescribers to ensure the access and use of 005. Medical science liaisons will play an important role. These greater and deeper scientific interactions to provide education on the disease and education on the product with KOLs and with the prescribing physicians. And then finally, customer support reps will play that important role of support and sales interactions with the physicians. In addition, these roles will also play a key part in ensuring the availability of ANX005. IVIG, more readily available in hospitals. Although over the last couple of years, we have heard about some supply shortages on -- in general, IVIG is readily available in hospitals. We're going to take the issue of availability off the table for hospitals by taking 3 approaches. The first is there are hospitals who will see GBS patients every couple of weeks, every month. Fully expect they will want to have this on hand and actually will stock ANX005. There are other hospitals who will see patients less frequently, maybe every couple of months. And from those hospitals who may be hesitant to stock ANX005, we'll have a consignment program. And so we'll have ANX005 available to them, and as the GBS patients come in, when they use it, that's when they'll pay for it. And then finally, hospitals that see patients far less frequently. With those hospitals, we've worked with a number of different vendors who have a service where they just call up a number and within hours, we can ship that product, ANX005, to these hospitals, so it's available. Because again, one of the advantages of ANX005 is that day 1 infusion rather than waiting 5 days to start to get better. And so we want to capitalize on that through the availability of ANX005. In addition -- next slide, please. These sales commercial teams will play an important role in reinforcing the clinical benefit and the patient outcome benefit of ANX005 with the entire care team from the emergency and intensive care team who see these patients initially to the neurologist who are the prescribing physicians, to the PM&R team, who've seen them long term from a rehabilitation perspective, we want to reinforce those benefits. The emergency room and intensive care team will see these benefits probably first by fewer patients ending up in the ICU, fewer patients on a mechanical ventilator, and to be able to reinforce what they're seeing with the neurologist. The PM&R teams hopefully will be seeing patients getting better sooner and not having the impact of being on -- being in the ICU as much or being on a mechanical ventilator. And so we want to make sure these benefits are reinforced across the care team so they can see the total benefit and the total opportunity for patients to get better sooner. So while this highlights the clinical benefits for patients of 005, on the next slide, I want to highlight the value-based benefits of 0.05. On the slide -- on the left part of the slide, I want to introduce you to Shane, who is a GBS patient. And what he told us is his GBS was so severe, he had to relearn how to crawl like a baby. And he crawled for 8 or 9 months, and then it took him 2.5 years to learn how to walk and then he had 5 years of physical therapy. Just imagine the emotional and physical toll that, that took on him and on his family, but also imagine the costs associated with that. These costs are significant for the care of these patients: 25% on a mechanical ventilator; 40%, admitted to the ICU; 20%, not able to walk after a year; 10%, so severely impacted, they're permanently disabled and can no longer work; and that 5% mortality rate that unfortunately for patients, has not moved in decades. This -- in -- together, these direct costs and the indirect costs lead to significant total economic cost for the U.S. This $2 billion number is actually quite dated and conservative. We're going to be working to update this number, but it's from 20 years ago, where the assessment -- the best that we have of direct and indirect costs was $2 billion annual costs in the U.S. And we can see this in our claims data analysis where we have seen patients who their total cost of care was $2.5 million. We've talked to hospitals in Europe who call these million-dollar patients because that's how much they're costing within the system. And not only the direct cost, but as we've highlighted, those indirect costs on the ability to work and the impact on the caregivers. So we are hopeful of the potential of 005, not only to provide the clinical benefits but also the value-based benefits and actually reduce the cost to care for these patients. So I want to finish where I began by first saying, we are excited about the opportunity and the potential to bring a new treatment option to patients who have gone decades without seeing a new option. And the second point that I want to share is we view this as a significant blockbuster commercial opportunity, and we're preparing for that, and we're excited for the opportunity to help these patients who are in need. With that, I'll turn things back over to Doug.

Thank you, Michael. Really nice job. Well, we hope today was informative and has helped you appreciate that GBS is a devastating disease with significant unmet need for patients and the health care system. Indeed, the lack of improvement in mortality rates alone over decades with standard of care highlights the high unmet need for rapidly intervening treatment in a condition afflicting over 20,000 people annually in the U.S. and Europe. As you heard today, we've achieved several important clinical milestones as well as regulatory milestones for ANX005, and have several key ones upcoming, including reporting pivotal top line data in Q2. We also anticipate data from our real-world evidence comparability protocol with IGOS in the first half of 2025 to support a planned BLA submission. With strong Phase III and real-world evidence comparability data, ANX005 is exceedingly well positioned to be the first FDA-approved treatment for GBS patients and further us of our mission to thrive by helping patients get better sooner and more completely. We thank you all for joining us today, and I also want to sincerely thank all of the patients, families, and study staff who are helping make ANX005 GBS program possible. We'd also like to thank the GBS|CIDP Foundation International, IGOS, and countless advisers, including our speakers here today for their continued support and partnership. With that, I will now ask the operator to begin our Q&A session. Operator, please open the line.

[Operator Instructions] And with that, we'll take our first question from Derek Archila at Wells Fargo.

Just a couple from us both for management and some of the physicians on the line. So I guess first off, just in terms of -- for ANX005, would you think that this falls under the FDA's guidance for rare neuro diseases? I know that was largely focused on ALS, but I'm just kind of curious if you feel that this would fit there. And what type of coordination does that afford you on the regulatory front? So that's 1 question. And maybe for the physicians. I guess how should we think about GBS patients, the symptomatology and ultimately, the underlying driver across the different regions, different countries? I know you guys pointed to some of the IGOS data, but maybe you can just expand in terms of how these patients typically do with IVIG treatment and overall outcomes.

Thanks, Derek. Really good questions. With regard to the first question and the FDA guidance on rare neuro indications, we certainly -- we'll be having those discussions with the regulators on that. GBS meets many of the criteria. So of course, it's managed through the neuro division in the FDA. It's a rare disease which is debilitating and underserved. And so we'll come back in time with more information with regard to that. But we are certainly encouraged by that guidance. I think that GBS checks many of the boxes as it relates to that. With regard to your second question, maybe we will start with Dr. Willison and also hear from Dr. Cornblath.

Yes, Derek. Thank you for that question. The incidence and prevalence of different types of Guillain-Barré Syndrome have been studied quite extensively in most parts of the world, with the exception of Africa where there's very little data at the moment. But it's quite clear that all forms of GBS occur all over the world, albeit with slightly different frequencies. And one of the drivers between these differences is the background of infections, in particular places that leads to the disease, for example, in some countries, Campylobacter jejuni enteritis is extremely common. And this is one of the major precipitating causes of Guillain-Barré Syndrome. So in countries where Campylobacter has a very high incidence, you're more likely to have more cases of Guillain-Barré Syndrome. For example, you might have recently heard of 2 enormous outbreaks of Guillain-Barré Syndrome in Peru, 1 last year and 1 in 2018, which were driven by epidemics at Campylobacter.

And Dr. Cornblath, would you like to add anything or we can move to the next question? Just wanted to give you an opportunity.

No, I think Professor Willison summarized the data well.

The next question comes from Anupam Rama at JPMorgan.

Just 2 quick ones. Maybe for the KOLs on the line, maybe you can expand on a little bit like what your experience and outcomes have been with patients when you do use IVIG and where you think ANX005, pending the clinical trial, keeping a similar profile could be in the treatment paradigm? And then maybe 1 for Lisa, just in terms of where you think the community's awareness is currently on ANX005? And what's being done to kind of educate the community on the product?

Yes, really good questions, Anupam. Dr. Cornblath, maybe we'll start with you this time.

So yes, thanks. We have IVIG because it was originally shown that plasma exchange was better than placebo, and then it was shown that plasma exchange and IVIG were equivalent. So there is a body of knowledge that we have that says it's better than nothing. But we also know the downside, which was presented well by Hugh, showing that 20% at the end of the year, 20% of people are dead or unable to work independently. So we know it's effective treatment but it's only partly effective. And the mechanism of action of IVIG is multimodal, but small in every one of its modes as opposed to shutting down complement, for which now there's 20 years or so of scientific evidence that it's a major player in this field. I think many people among physicians would be very excited about a very targeted immunotherapy like we're used to seeing in multiple sclerosis and in MSOD. All other forms of autoimmune...

Looks like David froze. Maybe Hugh, I'll give you an opportunity, if you'd like to also weigh in on the question on IVIG use.

Yes, yes. Thanks for that question. I agree with what David has said. One thing that we see in clinical practice is that many patients continue to deteriorate on IVIG treatment. And of course, this is hugely disappointing for us because there's nothing else that we can do. So patients carry on getting worse despite being on IVIG. And another frustration with IVIG is that whilst the clinical trials have clearly shown it is effective, it does take 5 days to give. And so you're sort of waiting to achieve what we think of as the maximum therapeutic effect over 5 days. And time really matters in the disease. And I think one of the advantages of having a very prompt and aggressive treatment that has its full therapeutic impact within 24 hours is that you can really have much more of a possibility of arresting the illness at a very early stage.

Yes. Thanks for that, Dr. Willison. And then maybe, Lisa, over to you and the question on awareness with regard to new potential therapies in the space, including ANX005.

Sure. Thanks, Doug. So we're so fortunate Annexon has been involved with us and has supported a lot of our initiatives, including our upcoming awareness month for the month of May. We do a lot to what we call demystify big pharma. So we try to establish ourselves as the place of trust, and we use experts in the field like Dr. Willison and Dr. Cornblath to add their comment, add articles for our newsletter with a 30,000 circulation base, at our educational events where we have about 500 patients and families attend. And we always have a session on current research, one of the most popular sessions. So this type of work would be mentioned and discussed there. As well, our medical advisory board, again, Dr. Willison and Dr. Cornblath, are all available for physician-to-physician consultation. So when you have a physician or a patient that's diagnosed with a physician that maybe hasn't seen a lot of this kind of disease, they can -- we can facilitate direct communication to one of our medical experts. So we're really trying to kind of spread the top-level education around it. Thank you.

The next question comes from Philip Nadeau at Cowen.

Two from us. First, in terms of the real-world evidence that you're collecting, what parameters, in particular, is the FDA going to look at for comparability between your population and the U.S. population? And is there any risk that those perimeters aren't met? And then second question, in terms of the Phase III design, you highlighted some novel elements of the design in the prepared remarks. Could you go into a bit more detail as to what factors of the trial design do you think set the trial for success, contrasting that again with other trials we've seen in the past for GBS such as Soliris' failed study in Japan? We're curious what you think the most important elements of the design are that would predict a better outcome than, for example, Soliris had.

Thanks, Phil. Really good questions. With regard to real-world evidence, maybe I'll invite Dr. Willison on that. He had a slide on prognostic factors for GBS that are important to consider in establishing comparability between patients across the globe. And I don't know, that was if he care to kind of elaborate on that.

Yes. Thanks for these questions. Have we got David back yet?

Yes, I hope so.

David Cornblath.

I turned off my video.

Yes. I mean, David has really been involved in the Phase III trial design and the FDA discussions more than I have. So can I pass it over to you, David, to...

Sure. Yes. So maybe we could go to that slide of Hugh's? So the 2 questions were kind of wrapped up. So the first one is about the comparability data. So what we've decided to do is use the standard and well-known prognostic factors as shown on the slide you're about to show, where we can go into the IGOS database and essentially begin to pick and choose from nearly 2,000 patients and essentially match them up for every one of these, if you will. So we can find patients who match on some score, disability scale, age, et cetera, that you see there, and we're about to measure serum neurofilament light in the IGOS population and the owner did some compound action muscle potential. So we feel from the IGOS population, if you will, minus the patients from Bangladesh as we're not going to use them to match against themselves, we can find patients to match. And that exercise is beginning just now. So let me turn to the second one is, and we actually have a backup slide, I think it's the next to last or last backup slides, where I can more easily speak to the Alexion material. Next one, I think. Yes, there you go. So if we can show that. So this highlights in somewhat anticipation of your question, and hopefully you can see this, what we believe are the differences. So the first is, of course, the mechanism of action. Eculizumab blocks down at C5, while the ANX005 blocks the entire pathway. And as Hugh also showed you in some of the schematics, we think that this is an important difference. In my view, the 2 most important differences are in the next 2 bars across, which are the mean time ones that from weakness to treatment. And although the Alexion group has not published as far as I know, they did have a poster, and it appeared as though the treatment time at which eculizumab was delivered was over 7 days on average. And if you think back to the slides that Hugh showed, you want to get that treatment in early during the active phase of the disease, and that's what the Phase III trial did with, I think, the average is about 5.5 days or so. So that's a substantial difference. And the last very significant difference is the Ms. So if you do a GBS trial of 57, you just can't be sure that the 2 groups are matched, and you can't be sure that you have enough numbers to show that there's a difference even if there is a difference. And that's very different than the next Alexion trial -- sorry, the Annexon trial, which has 3 robust arms with a total line of 241. So those are the 3 main things. The last one is the stratification of course. But that goes into balancing of the groups and in the analysis. But the designs are completely different, and it's not surprising that the Alexion trial failed.

That's very helpful. And we look forward to the data.

The next question comes from Andrew Tsai at Jefferies.

Appreciate you hosting. It's been very helpful. So maybe for the first question. We're obviously going to be looking for the top line data in Q2. So just wondering if you can share just a little bit more granularity how the primary endpoint will specifically be analyzed and shared. So do you break out for us the percentage of patients from baseline scoring 3 to 5, improving to bucket 1 versus placebo and do you break out the same percentage of patients improving the bucket 2 versus placebo? And in terms of a win, as long as each of those 2 buckets show a twofold benefit over placebo, is that positive? And is it fair to assume that if only 1 of those 2 buckets shows a twofold increase, then the primary endpoint isn't positive? So just some additional color would be helpful.

Yes. Maybe I'll start and I'll invite Ted and the KOLs to also weigh in as you like. So the twofold better -- shift to better on the scale is across the entire scale, Andrew. So we are looking to see really a twofold shift to better at the end of the scale in the category, as you see here in the good state, as well as less patients in that severe disabled category. So -- but the twofold is really a combination across the entire scale. Ted, I don't know if you like to weigh in on that.

Yes. I was just going to say that as Doug said, you're going to have more in the first box and less in the third box, and you combine those 2, so it increases the power of the study. So if one of the -- you would expect both of them to go into the direction that you want. But if one does more so than the other, it can make up for any deficiency you have in that bucket. So that's why there's greater power. So it's not a simple, yes, you made it there and no, you didn't make it there, you combined 2 of them for the statistical analysis. Yes, I think that's the outset.

And am I able to ask another follow-up question?

Yes, certainly.

And so at the end of the day, as we just think a little bit more about the primary endpoint, what would the placebo response be in your view for patients going from baseline to each of these 2, good state of health and disabled?

Yes. We have not shared our specific powering calculations with regard to placebo. But what we have talked about is how we've gone about developing what that number is anticipated to be. So we were able to leverage placebo activity out of the IGOS database that you've heard mentioned here well. There's also a separate cohort study out of Bangladesh that has placebo patients. And then, of course, in our Phase Ib study where we have placebo. All of that data culminated in our assessment of how we anticipate placebo will do in the Phase III, and it's consistent with what we see in our Phase Ib.

The next question comes from Tazeen Ahmad at Bank of America.

I just want to go back on sort of why FDA is asking for this comparability study. Is it because there are pretty meaningful differences in how patients ex-U.S. are treated? Can you just give me a and go over those major differences, if there are?

Yes. Dr. Cornblath, can I invite you to participate on this? I'll start at the highest level. The reason for the comparability or real-world evidence is to demonstrate comparability of patients who are being treated in this study outside of the U.S. with the patient population in the U.S. So obviously, the FDA's mandate in charge are U.S. citizens, and they want to be certain that whatever effect we are having on patients outside of the U.S. would be comparable to what you would anticipate in the U.S. But maybe Dr. Cornblath, you'd like to add anything to that.

No, Doug, I think you got it well. There's a whole FDA issue about using patient, getting approvals for drugs in the U.S. on outside the U.S. patients only. And this is the way to do it to show that it is substantially the same, that is the drug, the disease and its effects are similar to what can be expected here in America. Is that helpful?

Sorry, is there a difference in the results that you would anticipate getting from U.S.-treated patients because of, I don't know, anything that could be different in terms of how they've been treated before or at what stage they're diagnosed? And then also, sorry to ask again another question. But how easy is it to diagnose patients within a 10-day period, do you think?

Yes. So the first one is that in the United States, and in fact, if you look at the IGOS data worldwide, very few, very, very few patients who are at these disability grades. As I said, 3 through 5 are not treated with immunoglobulins. So almost everybody worldwide where immunoglobulin is available who would be eligible for this study is treated with immunoglobulin product. And so because there are no immunoglobulin-treated patients in the pivotal trial, the idea is to compare patients treated with ANX005 to those similar type of patients now treated with immunoglobulin, if that helps.

And the other piece, I think maybe what you were asking, Tazeen, is a bit on would we expect differences in outcomes in patients in the U.S. versus outside of the U.S.? Does that help summarize part of your question?

Yes.

Yes. Well, this is -- where the prognostic factors for outcomes are really, really important. The key prognostic factor for how a patient is going to fare with GBS is shown here on this slide is your baseline muscles are as measured by MRC. And this has, again, been well studied and published through IGOS and with some of the experts on the call here today. And so we don't anticipate that if a patient who enters into the study with a baseline score of say, 30, in Southeast Asia would progress significantly different than a patient who entered into a study in the U.S. with a baseline score of 30, assuming the same treatment therapy. So I don't know if that helps. I don't know if Dr. Willison, you'd like to add anything to that or?

No, I think you've summarized that very well. And I think the outcomes are surprisingly even when controlled for these factors across the world. These factors, these prognostic factors have come out in a lot of different geographical regions. Tazeen, with respect to diagnosis, I think Guillain-Barré is, if you watched an episode of House, you'll see that Guillain-Barré Syndrome is one of the first diagnoses that comes to people's mind when a patient presents the casualty with acute symmetrical paralysis. And the awareness of the disease, particularly through organizations such as GBS|CIDP FI has improved hugely over recent years. So I don't think delayed diagnosis is really the issue. I think what really matters, Tazeen, is having suspected the diagnosis and come to an identical decision about the level of certainty of that. The main thing is getting treatment delivered as quickly as possible. And I think that is the challenge that we all face is making sure that if a patient comes in on a Friday evening, that the treatment isn't deferred till Monday, but that it's given on Friday evening at midnight. One of the reasons why plasma exchange has been largely replaced by IVIG is to do with that, is to do with the delay and the getting the plasma exchange unit into gear takes a lot longer than getting immunoglobulin delivered from pharmacy. And I think that this sense of urgency is something that we all want to get into the program of care for GBS patients, this sense that this really is a medical emergency, which needs prompt and complete treatment at the earliest possible opportunity.

The next question comes from Ananda Ghosh at H.C. Wainwright.

I have 2 questions. The first one is, is there any data on the misdiagnosis rate of GBS in the U.S.? And then the next question is, what is the rationale -- with respect to the diagnosis, what is the rationale between the geographic distribution you see in U.S. standard around particular center or particular zones in the United States? That's the first question. And I have a follow-up question on the trial design.

Thanks, Ananda. I didn't quite get your first question. I got the second one. Could you repeat the first one?

Yes, what's the -- is there a -- like what's the misdiagnosis rate for GBS in U.S. or you hope, given the heterogeneity of the disease?

I see, the misdiagnosis rate. Yes, that's right, Dr. Willison, please.

Yes. So if you look at the clinical trials and you say that the clinical trials are done by experts and they then give everybody immunoglobulin, this sort of misdiagnosis rate, if you will, is somewhere around 2%, 3%. Some of those you couldn't make the right diagnosis because they look like GBS and then they go on to be a chronic form of the disease, but the misdiagnosis rate once a physician says, "This is GBS. I'm going to give immunoglobulin," is extremely small. The second one was about the geographical distribution. I mean, that's run by population. And then it's also run by the fact that most community hospitals, if you will, are going to push patients toward larger university hospitals just because of the comfort level that the larger hospitals will have in treating people with GBS.

Yes. And Michael, would you like to weight on that at all?

Yes. I would just add to that point is it's the indiscriminate nature of the disease that it could strike anyone at any time. And so everyone has an equal chance of developing the disease. And so therefore, where you see large populations with that equal chance, you're going to end up having more patients who have GBS than when we have areas of less population. So it's just concentrated based on where the people are concentrated on, and that's where these large hospitals are in the academic centers as well, which enables us to have that focused approach.

Got it, makes sense. My second question is on the trial design. And I just wanted to -- very similar to Phil's question. What are the -- what were the trial design challenges with respect to plasma exchange or IVIG prior to your way of designing this trial where you used concepts like early onset or use of [ envigos ] or stratification? So just wanted to get a more deeper insights into the trial design with respect to historical trials in this space.

Yes. Dr. Cornblath, Dr. Willison, we'll turn those back over that one over to you as well. So I guess the history of IVIG trial designs and where this might be different. I think you highlighted, Dr. Cornblath, some of the differences with eculizumab study. Do those also apply to historically IVIG types of trials, et cetera?

Yes. So the main driver of the design overall and the location of this trial was how you could design a trial, given that the standard of care in most of the West is IVIG. And the question was, could you design a trial or would you want a trial in which there was either an IVIG comparator arm? Or more importantly, would you have to do a trial with ANX005 plus IVIG versus the other IVIG. And so to move this forward quicker, we took advantage of the fact that there are many places around the globe where IVIG is not available. And one of the main ones is Bangladesh, where there also happens to be an extraordinary, the excellent trial group who's participated in multiple trials before. It's been an active participant in IGOS, has a dedicated trial unit and therefore, the trial was designed as a placebo-controlled trial in a location where it was ethically acceptable to use placebo. Does that help?

Got it. Yes, please.

I have a -- it's Hugh here. I have a very quick follow-up to Ananda's first question. You're right about this diagnostic uncertainty. And in fact, there is a very well-trodden history to this excellent set of certainty criteria called the Brighton criteria, which published in Bahrain. I think that it's very unusual to have this rate of a few percent, which David has quoted, has come out in IGOS as well. It's very unusual to have patients who were diagnosed as having something else and it was then concluded they had GBS. It's almost always the other way around. And so most patients would be given a preliminary diagnosis of GBS, which might be subsequently changed. And I think there's a lot of -- so it happens that way around rather than the other way around. And in fact, quite a few patients would be treated for suspicion of GBS with intravenous immunoglobulin as it currently stands and yet later find out to have something else, but not a lot is lost through that approach.

So the next question comes from Joseph Stringer at Needham.

Two from us. Wondering if you could summarize any retrospective analysis that's been done on the proportional odds improvement on GBS DS or response rates for historical trials looking at IVIG and GBS? And would you consider that a good comp for success for the ANX005 Phase III readout? And second question is on Phase III trial design. Does the trial include and/or stratify by GBS subtypes? And is there a mechanistic reason that 005 would have different effectiveness in these subgroups?

Thanks, Joe. Maybe we'll start your second question first and the subtypes that at the high level, the trial was not stratified by subtypes. It is stratified by the key prognostic factors, which is not subtypes. It's things like MRC, time to treat it from symptom onset cetera. But Hugh, maybe if you'd like to weigh in on the subtypes discussion and stratification or anything around that.

Yes. The -- everybody recognizes that the far ends of the spectrum, there do appear to be patients who have an extreme of a subtype. Having said that, there is also a huge body of evidence that many patients have intermediate forms and another body of evidence which suggests that patients can start with 1 subtype and then morph into another subtype and vice versa. So this whole issue about subtyping is fraught with conceptual and practical problems. And I think that to introduce it into a clinical trial create -- has the potential to create less clarity rather than more clarity. You can see from the right-hand panel here, for example, that if you measure the extent of axonal injury, the AIDP, which is the far left column, is a patients classified physiologically as a demyelinating subtype. And yes, it's very, very clear from that, that they're releasing axonal debris into the circulation at pretty much the same rate as the patients diagnosed of the axonal subtype. And I think that manifests evidence that subtype classification isn't necessarily helpful in a clinical trial context.

Joe, and I think your second question related to the assessment of the endpoint using proportional odds for the placebo group. First thing I will say is this is the first study using proportional analysis with GBS in a randomized study. So the work that's been done here has really been pioneered by what we are doing. And we have done work with regard to IVIG using this proportional odds analysis, which again, went into how we powered the study. But we cannot point you to any historic publications or anything of the like that, at least that I'm not aware of.

Yes. So let me make 2 comments. The next one, the -- to go to the first point is if you look at those slides of the images from the human autopsy material, which were done at Hopkins, you can see that complement is active and important in both forms of the disorder on the far left, the so-called AMAN form and on the far right, the AIDP form. So that's the main reason why we don't think that it's necessary to put them apart. There's a whole universe, which I've been heavily involved, just trying to figure out what are the right electrophysiologic criteria that separate the 2 groups. Everybody thinks it's so simple. But in fact, it's not and there are lots of proposals for how to separate them. The last point about proportional odds is I would turn your attention to the SID-GBS trial. It's been published and it's not anywhere here, but the Annexon people can get you the reference or I can by Pieter van Doorn. And you can see the proportional odds used there. But in a subgroup of patients who had a poor prognosis where the question was, does the second dose of immunoglobulin help? So Pieter van Doorn does have the data for a large group of patients who have been treated just with IVIG, but it's not been subjected, if you will, to a proportional odds against another group, if that helps.

That's very helpful. Yes, it's really good. So a bit of a proportion of that data with regard to IVIG, but not placebo. Any follow-up questions there, Joe? I just want to make sure we covered you before we continue on.

No, that's very helpful.

And we have one last analyst in the queue, so we'll have the next question comes from Pete Stavropoulos at Cantor Fitzgerald.

Hello, Annexon team, and thank you for hosting this event and taking our questions. Pediatric neurologists we have spoken to, they stated that the pediatric population also experiences GBS post-infection, non-occasion vaccine-induced, and they treat them with IVIG. And thank you, Ms. Butler for sharing your experience. I just want to ask Dr. Willison and Dr. Cornblath, how often is it seen in the pediatric population and your thoughts on utilizing 005 in peds? And for the company, do you have any plans for a pediatric population? And if so, what do you believe the regulators would like to see? And also, does the 7,000 U.S. patients cited in the presentation include the pediatric population?

Yes. Maybe first of all, you asked a good question there. So last one is always interesting. Any thoughts, Dr. Cornblath, Dr. Willison on numbers of pediatric patients with GBS?

Yes. I mean the data around, it's a fraction compared to the adults. I mean, it's a very, very small number compared to the adults. I'd tell you about an interesting study that was done and that will play into how the attritions might consider 005. And that is a number of years ago, a fellow in, I think, it's Switzerland did a study in which he gave IVIG to kids over 2 days rather than the adult dose of over 5 days. And in fact, it turned out that the major motivator of this study was to get kids out of the hospital faster. The problem was when you gave IVIG over 2 days to kids, the relapse rate, like you heard for Lisa's son, in that study was about 23%, while giving IVIG over 5 days, the relapse rate was 0%. So among the pediatricians, there is an enormous pressure to get kids in, treat them and get them out. Unfortunately, giving IVIG in 2 days versus 5 didn't work. So if there were an alternate that would give treatment 1 day in a pediatric population and you could get a kid either out or to a rehab unit, that seems to me to be a big win. But again, the numbers are really small.

And then Pete, just with regard to the regulatory question in pediatrics, we have not engaged significantly on that topic. There have been initial discussions and a bit of feedback on that, but more to do on that. As Dr. Cornblath just made clear, the preponderance of this disease is in adults. So that's where we're focused initially.

Okay. And then just -- do I have 1 more question?

Sure. Absolutely.

So as briefly touched on before, but like when you think about the pathobiology and the disease course, the mechanism of action of 005 and the criteria that the patients be dosed within 10 days of symptom onset, and I believe in the Phase Ib, it was around 8 days in treatment from onset of symptoms. Just want to ask Dr. Willison and Cornblath to speculate as well as a company, if you have -- if you save that time down from symptom onset to say, 4 or 6 days, is it possible to see a greater efficacy for 005 in the Phase Ib? And what learnings from the Phase Ib have you implemented to try to shave that time down?

Maybe start with the second question, and I'll turn it over to the KOLs. We just really intently focused on giving patients in sooner in the Phase III. Recall that the Phase Ib was a safety dose ranging study, where we also looked at exploratory efficacy measures and saw a really strong, consistent effect as Dr. Willison took us through. However, in the Phase III with the understanding that time from symptom onset was a key prognostic factor. It was just a significant focus by our clinical team to ensure the sites understood the import of it and made sure that we got patients enrolled in the study and dosed as rapidly as possible. So we did see improvement in our Phase III over the Phase Ib with regard to that. And just your first question on how important that could be in outcomes, maybe Dr. Willison, you can touch on that as well?

Well, Pete, I think you've answered your own question very well. And I think speed of delivery of treatment is incredibly important in Guillain-Barré Syndrome. And to be true for probably something we haven't really thought about enough in the GBS community, in part because we don't have a targeted monospecific part, monospecific pathway therapy yet available to test that in. I think that if 005 does come through the Phase III trial as a successful drug, there will be huge pressure and enthusiasm among all of us to try to deliver it at the first possible moment in the clinical course of the disease, it makes absolute pathobiological sense that quicker you treat these patients, the better.

Thank you. This concludes the Q&A session. I'll turn it back to Doug for concluding remarks.

All right. Well, listen, thank you, all. We greatly appreciate you joining us today and your attention and good questions. As we said at the outset, this is indeed an exciting time for Annexon and yes, the GBS space as a whole. We look forward to continuing engaging with you as we move closer to releasing the top line data. And please let us know if you have any follow-ups, just contact the company directly. Thanks so much. Thanks again to our speakers, and we wish you all a really nice Friday. Take care.