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

Good morning, everyone, and welcome to Annexon's series on C1q [indiscernible] complement-mediated diseases. I'm Doug Love, CEO and President of Annexon Biosciences, and we're delighted that you have joined us today. Today's session is the first of 3 C1q teach-in series that we will be conducting over the next few months. This one is focused on our autoimmune therapeutic franchise, where we announced last week the addition of 2 new indications into the portfolio, lupus nephritis and multifocal motor neuropathy, or MMN. We will spend today's session discussing these 2 new indications. In the early [indiscernible] C1q series, focused on our neurodegenerative therapeutic franchise and the role of C1q in complement-mediated neurodegeneration, there we'll profile our 2 lead indications, Huntington's disease and ALS. And then finally, we will conduct our third C1q series later in the fall, focused on our ophthalmic therapeutic franchise and the role of the classical pathway and C1q there and spend time discussing our lead indication, geographic atrophy, as well as other neurodegenerative ophthalmic indications that we're quite excited about, including progressing glaucoma on top of IOP-lowering drops. So with that, we shall dive into today's session. On Slide 3, just highlights. We will be making forward-looking statements, and we invite you to see our materials on our website. In terms of the schedule for this morning, I'll spend a bit of time just grounding you on Annexon's approach to establishing a new class of complement medicines by targeting upstream complement in the classical pathway. From there, we will spend time discussing the classical pathways mechanism of action in antibody-mediated autoimmune disorders as well as our precision medicine drug development approach, which we think enhances our overhaul likelihood of success. The bulk of our time will be spent on the 2 new indications, lupus nephritis and MMN. And on the back end, we have time for a Q&A session, where we invite your questions so that we can have a robust dialogue. With no further ado, we shall dive right in. As you are aware, Annexon is focused on pioneering a class of new complement medicines by stopping C1q and the classical complement pathway right at the start, as depicted on the left of this slide. In so doing, there are 3 unique characteristics of our platform. One, we are targeting enhanced efficacy and safety in the indications we are pursuing by blocking all downstream inflammation and tissue damage mediated by the classical pathway early in the disease process. Only by blocking C1q are you able to do so. Secondly, by blocking C1q at the start of the pathway, we are tackling 2 distinct disease processes: one, the well-known antibody-mediated autoimmune disorders, which we are discussing today; and the second, complement-mediated neurodegeneration, which is the discovery of our scientific Co-Founder, Dr. Ben Barres, and which we will discuss at our second teach-in series in the early fall. As a result, our platform approach has pluripotential across 3 therapeutic areas: autoimmune, neurodegeneration and ophthalmology. We're, of course, leveraging synergies and learnings across all 3 of these indications for these therapeutic areas to increase our overall likelihood of success of bringing game-changing therapies to patients suffering for devastating diseases in each of these 3 areas. Finally, by targeting C1q right at the top of the cascade, we've been able to develop multiple delivery solutions to fully inhibit the cascade down through C3, C5 and C9 with diverse routes of administration. So we have drug candidates that are infused IV, we have intravitreal administration, subcutaneous approach, and soon on the horizon, a first-in-kind oral small molecule approach for which we anticipate an IND later this year. All 3 of these characteristics that make up our platform, we think are distinct from targeting complement downstream, and we'll talk more about that as we progress this morning. Now it's important to establishing a first-in-kind platform approach is to be rigorous and intentional in doing so. And we have done exactly that. We have deep domain expertise in the classical complement pathway, dating back to Dr. Ben Barres' discovery of the role of C1q on the neurodegenerative side back in 2007. Since then, we've developed drug candidates against all of the components of the classical pathway and have a real strong understanding of their impact in the disease process. Secondly, we have selected indications that have the highest biological rationale. We're doing that rigorously with objective biomarkers, really only selecting indications where we can assess excess aberrant classical complement activity in each of the indications for which we are pursuing. Again, we will show you data on that. Thirdly, we're advancing this portfolio in parallel. So we are conducting studies across autoimmune, neurodegeneration and ophthalmology, again, learning and taking synergies across all of those programs to better understand this pathway approach and increase our likelihood of success. We're leveraging a precision medicine biomarker approach to select the right patients. Again, these are patients with excess classical complement activity and other characteristics, which we will talk about, to set dosing in various compartments in the body, brain and eye and to assess in our early clinical studies our drugs' impact on the disease processes. Finally, as I said on the prior slide, we've developed a suite of fit-for-purpose drug candidates that block complement in diverse tissues in the body, brain and eye. So we've taken a holistic, rigorous approach to establishing this first-in-class portfolio, and we're quite excited about that. We also are using this approach as we advance into or expand into additional indications that meet this criteria. And I'm pleased to say today that we have indeed established a strong foundation with regard to our classical complement platform. We recognize that this is a unique platform with these 3 components and it's a lot of information to take in, and so we want to ground you on what we know today about this approach. First thing to call out is we have indeed treated roughly 200 subjects with 3 distinct clinical drug candidates in both orphan and large patient populations across autoimmune, neurodegeneration and ophthalmic indications. And we have several key learnings. First and foremost is we have observed very consistent translation of our preclinical data to the clinic. That's, of course, important in selecting the right dose as well as ensuring that we are seeing the impact on the disease process that we desire to have a meaningful impact on patients in the clinic. All of our drug candidates have been well tolerated in the studies thus far. And we've achieved full C1q inhibition in all of the compartments for which we've looked, so that's the periphery in the blood, across the blood brain barrier and, of course, in the eye. In each of these instances, we've done so by assessing objective biomarkers, and we'll show you some of that data. And importantly, we have demonstrated full inhibition of downstream classical complement activity, again, through C5 -- C3, C5 and C9, which we think is quite important to stop this enzymatic amplification right at the start and potentially provide enhanced efficacy and safety for the patients who are seeking to benefit. And finally, we've demonstrated impact in autoimmune neurodegenerative disease processes with our drug candidates, which is really quite important, including establishing proof of concept in our most advanced program, Guillain-Barré syndrome, in a placebo-controlled trial. So where we are today is, in effect, on the launching pad, conducting 7 mid- to -- late to mid-stage clinical readouts that will read out over the next 2 years. We're excited to create value for patients and for shareholders who are on the journey with us in that regard. Our pipeline is broad and deep and wholly owned of classical complement inhibitors. Indeed, as I've said before, it consists of 3 therapeutic franchises. We're conducting 7 clinical trials with 5 drug candidates with 4 different routes of administration, again, all inhibiting the target and preclinical-stage candidates that are currently underway. Now importantly, each of these studies represented on this trial are slated to be completed over the next 2 years. And so we have meaningful near to midterm value catalysts across this portfolio, which we're quite excited about. Today, we're focused on MMN and lupus nephritis, and so we will punch deeper into that. But before getting there, I think it's important to note that while we prepare a play for the near term and making a difference in patients' lives and creating value for others, we do have line of sight to significant additional opportunities in the mid- to longer term. Here, on this slide, just represents a snapshot of the many different types of indications that we believe are available to us as they are mechanistically related to our lead or beachhead indications. We have data in many of the indications on the left in the autoimmune space and are deploying a very robust precision medicine approach to identify patients, in some instances, that make up the entire patient population, such as in GBS and MMN or, in other instances, a subset of the population who have excess classical complement activity, such as in warm autoimmune hemolytic anemia and lupus nephritis. And Sanjay will take you through some of that. On the right, as it relates to neurodegeneration and ophthalmology, we have preclinical data in all of these indications and more. And so we're very encouraged with the outlook on our current portfolio and trials and the opportunity there and even more encouraged with the longer-term outlook for this upstream classical complement approach to make, again, a significant difference in treating these devastating diseases in patients. Finally, I'll close just by punching more directly into the autoimmune franchise for which, as I alluded to, we've strategically expanded into potentially higher-value indications. There is strong scientific rationale and unmet need for each of these indications, both MMN and lupus nephritis. As I've noted, we are leveraging a precision medicine approach in lupus nephritis, which we think is first in kind and certainly enhances the overall probability of success by really understanding the disease process and how the classical pathway plays a role in driving that disease process and shutting it down right at the start. And then as it relates to MMN, we're, of course, leveraging our GBS proof-of-concept data, MMN being very mechanistically related to GBS in many, many ways. And we will take you through that rationale. And so that provides us a thumbnail snapshot of Annexon and where we are today and where we're going. And with that, I am going to turn it over to Ted Yednock, our Chief Scientific Officer and partner in crime here, to walk us through our mechanism of action of C1q and the classical complement pathway in antibody-mediated autoimmune diseases. Ted, over to you, sir.

Thank you, Doug. Yes. So our interest -- Annexon's interest in C1q, of course, with Ben Barres, our Scientific Co-Founder. And he's the one who discovered that C1q recognizes synapses both in development and neurodegenerative disease where it drives synapse loss of neuroinflammation. But of course, it's been known for decades that C1q drives as a major amplifier of antibody function, and it drives antibody-mediated autoimmune disease. So our intention has always been to develop complement inhibitors both for neurodegenerative disease as well as for autoimmune indications as well. So we began in our early years by developing antibodies against all of the early classical components, including C1q. And we found that it turned out that inhibiting C1q was really the best way to fully inhibit the classical complement cascade. It's right at the top of the cascade, and I'll explain more about that a little bit later. So we began by taking ANX005 as our lead candidate into an autoantibody-mediated disease, Guillain-Barré syndrome, and Sanjay will be reporting or showing results from our Phase I study there. We've also taken ANX007, a Fab fragment of 005, into glaucoma patients with intravitreal administration, where we've shown full target engagement. And then today, we're going to talk about ANX009, and we'll present our first in-human study with that. This is a subcutaneously administered Fab fragment, which specifically inhibits C1q in the blood space. And so that will be as part of our advancing pipeline while these different fit-for-purpose drugs will have different indications, and we'll go into that in further discussion. Okay. Next slide. So our -- just a few words about C1q. C1q is the initiating molecule, the classical complement cascade. It binds to the cell surface to activate the cascade. In the case of autoantibodies or antibody-mediated autoimmune disease, C1q is recognizing these antibodies balance to the cell surface. It binds there and then it activates C4 and on down the pathway. An important aspect of this is that every molecule of C1q that binds to the surface activates multiple molecules of C4, which then leads to activation of multiple molecules of C3. So it's sequential amplification, again, one reason why it's so important to inhibit the first molecule of C1q binding up at the top. So when C1q binds, it anchors this whole pathway there. And each of these different components have different activities. So the early components of the pathway, such as C4, C3 and C1q itself are opsonins. That means that they're bound to the surface and they're recognized by macrophages to direct macrophage attack directly on the cell. And then the downstream components, C5 to 9 form a pore which interacts with the cell surface to cause membrane damage or cell lysis. So all of these pathways has a distinct activity. And by blocking C1q at the top, we're inhibiting all of them. Next slide. The point of showing this slide is because I want to really emphasize the surface binding of C1q. So shown here in the pictures, C1q is binding to the neuromuscular junction. This is all in autoantibody-mediated disease. So C1q is bind to the neuromuscular junction. In the middle, you can see C1q binding to autoantibodies on red blood cell surface. And then on the right, C1q is accumulating in the vascular filtration unit of the kidney or the glomerulus. And so by blocking surface binding, we intend to be treating neuromuscular indications such as Guillain-Barré Syndrome or hematologic conditions such as warm autoimmune hemolytic anemia or nephrology conditions such as lupus nephritis. Okay. Next slide. So using the red blood cell as an example here, looking at warm autoimmune hemolytic anemia. This is a disease that's mediated by both IgM and IgG antibodies against the cell's surface of the red blood cell. When they bind, C1q interacts with them. It then triggers the classical complement cascade. And you can see then that C1q and C4 and C3 are all on the surface of the red blood cell. And there -- that means now that the red blood cell is ready for recognition by macrophages, and they'll pull the red blood cells out of the circulation. Activation of C5 to 9 also causes membrane damage. And so if the cell isn't pulled out by the macrophage already, it will be lysed within the intravascular space, which happens to some extent in this disease. But mostly, it's macrophage on recognition. On the right, we're showing that looking at patient sera on red blood cells in vitro, we can -- we've -- our antibody, ANX005, blocks C1q binding to the surface as well as all of these downstream components, so C4, C3 as well as C5b-9. So again, blocking C1q at the top is blocking all of these activities. Next slide. So here, we're showing data from our Phase I study in Guillain-Barré patients, where we -- where this disease is mediated by IgM and IgG antibodies that recognize nerve components, such as GM1 ganglioside. At some of the surface of nerves, the antibodies bind, C1q recognizes that and activates complement. So in the right graph, we're looking at CSF from patients, and we were able to measure each of these kind of antibodies in different patients. So some patients have IgM antibodies against GM1 ganglioside, others had IgG and some had both. And in all cases, we were able to measure complement activation in vitro from these -- with CSF directly looking at GM1 ganglioside. Now -- so all of these have activity, that's shown in the box in the upper right with all the multicolored circles showing the different antibody isotypes. Now if we took blood CSF samples from these patients a few days after treatment with our drug, we found that all of these antibodies, they're still there in the CSF. But their activity is completely inhibited because the drug has gone into the CSF and fully inhibited C1q. So this is a demonstration of how we're able to block C1q actually by treating patients. The next slide. So I've really emphasized how C1q is -- it's important to block it up at the top from an efficacy perspective because you're blocking all the components of the pathway. So blocking C1q, we get full inhibition of the classical cascade. Importantly, from a safety perspective, we're leaving the lectin in the alternative pathways, complement pathways in place for normal immune function. So we're really focused on diseases where C1q is the key driver of complement activity in antibody-mediated disease. And so by blocking C1q, we're selectively hitting the pathway that we want to affect and leaving the other ones in place. Excellent. Just to illustrate the point that I've been making about inhibiting C1q at the top. As I said before, we made a number of antibodies against different components of the early complement cascade. Showing in the graph on the left is our antibody against C2. It's an excellent antibody. It's as potent as ANX005. Under normal assay conditions, when people look at the classical complement pathway, they normally take human serum and they dilute it 1:100. And that's part of the standard assay. However, on the right graph, if you look under more physiologic concentrations of serum, in this case, it's diluted 1:3, ANX005 still fully inhibits the classical pathway, but Anti-C2 has completely lost activity. And the reason for this is there's a well-described, so-called C2 bypass pathway described in the literature in which, under high activation conditions, Factor B from the alternative pathway can come in and substitute for C2 and then allow this pathway to continue. So again, a single molecule of C1q bonds to the surface is going to drive these downstream components in an expanding fashion. We have similar results with Anti-C1s and Anti-C4, and similar results have been published for C3 and C5. So these downstream components, once the pathway is on track with C1q, it's really hard to stop the moving train. Okay. Next slide. So just to summarize what I've said so far. C1q binds to tissue of the surface, it focuses on the classical cascade activity right there. That activates all of these downstream components. And we can selectively block all of those by inhibiting C1q while leaving the lectin in the alternative pathway in place. And we can -- Anti-C1q is effective with both low and high complement activation conditions. Okay. So using ANX005 has really been the core of our portfolio. From there, we have developed additional monoclonal antibodies, ANX 05, 09 and 105, which we'll talk about in a moment. But we've also developed a very independent inhibitor based on the data and the knowledge that we have of the classical cascade. We've done a crystallography-based screen and identified an orally available small molecule, which we'll be talking about later. So first, a few words about ANX005 itself. Very high-affinity antibodies, 7 picomolar binding for C1q. And this turns out to be quite important, which I'll discuss. We know that it fully penetrates the blood brain barrier, fully inhibits the downstream -- or classical complement cascade. We've completed both 4 and 26-week toxicology studies in cynomolgus monkey. This is produced at Lonza. It's a very good high-level producing antibody. And as Doug was mentioning, ANX005 itself has been dosed in over 100 patients. In the next slide, ANX009 is a Fab fragment of 05. It's being developed for subcutaneous dosing and looks as though we will be dosing for twice a week. And this targets C1q within the vascular. ANX105 is a full antibody. It's a modified version of ANX005. It has enhanced dosing properties. And then as I mentioned, 1502 is the small molecule that we've identified in crystal-based screening. It's a very potent small molecule with similar activity to ANX005 itself. Okay. So just to summarize then. This is our portfolio. We have 005 is our lead candidate; 009 is targeting blood-based and vascular disease; 105 is for systemic autoimmune and neurological conditions; and then 1502 will be an orally available drug for autoimmune disorders. And 005 is really at the league advancing our pipeline in all these different disease indications. And so with that, I'm going to turn it over to Dr. Sanjay Keswani, our Chief Medical Officer here at Annexon. Thanks for your attention.

Thank you, Ted. So we're going to advance to the next slide. So as Doug and Ted articulated, our Anti-C1q platform has broad therapeutic potential in a whole host of autoimmune diseases. And we're targeting 3 specific disease areas within this autoimmune franchise: neuromuscular, hematology as well as nephrology. Now for all the diseases that we select in the clinic, we have evidence of aberrant classical complement pathway activation, driving disease either in the entire population or in a relevant patient subset that then we would identify and treat in the clinic. All these diseases also have high unmet need and a tractable clinical development plan. Now for the case of neuromuscular diseases, GBS is our lead indication, and we have demonstrated proof of concept in that disease. And that gives us confidence to initiate a Phase II study in MMN, or multifocal motor neuropathy, which is a mechanistically very related disease. Both GBS and MMN are autoantibody immune diseases attacking the peripheral nervous system. And we'll be speaking a bit more about that mechanistic overlap later in this presentation. In the context of warm autoimmune hemolytic anemia, which is our second ongoing Phase II program in autoimmune diseases, we're employing a precision medicine approach, essentially enriching for patients with classical complement pathway activation. And that should give us an increased response rate to our Anti-C1q therapeutic in the clinic. We'll be employing a similar precision medicine approach in lupus nephritis, which is another autoimmune disease that we'll be initiating shortly. So we're utilizing a precision medicine approach, which underpins our development strategy in autoimmunity. And this should increase probability of success in the clinic. And the reason we can do this is because we have access to the right tools and assays. So we can select the right indication, right patient subset, utilizing assays for classical pathway activation that we can employ with bio samples and in clinical trials. With respect to picking the right dose, we have access to target engagement biomarkers for C1q and the classical complement pathway. And I'll be showing examples of how we utilize these markets in the relevant bodily fluids, for example, blood for autoimmune diseases, CSF in the case of neurological diseases and aqueous humor for ophthalmology. Picking the right time is really important in drug development, and that relates to access to natural history data that we have for our patient population, specifically the behavior of key biomarkers longitudinally in these patients over their disease course. And selecting the right drug candidate, as Ted alluded, we have a whole slew of drug candidates that we can utilize in a fit-for-purpose manner depending on the patient population. This slide highlights some of the data that we've generated, utilizing biomarkers and tools to enhance probability of success. So on the left is a demonstration of our precision medicine approach, utilizing bio samples from well clinically annotated lupus nephritis patients. This was a result of a collaboration with Dr. Dall'Era at UCSF. And here, one can see that we identified a subset of patients with active lupus nephritis with a high degree of disease activity, whose disease is driven by a classical complement pathway activation. So this is a patient subset that we would recruit in subsequent trials in lupus nephritis. In the middle, we have an example of target engagement. This is data from our Phase Ib study in acute GBS, where we showed high engagement in the CSF in these patients. Now although GBS is a peripheral nerve disease, of note, nerve routes are important site of pathology and they're surrounded by CSF as they exit the spinal cord. So we're happy to demonstrate CSF target engagement as well as target engagement in the blood. And on the right, utilizing biomarkers objective measures of treatment effect results in cost-effective and efficient proof-of-concept trials. In this case, we have data showing neurofilament light chain reduction in acute GBS patients. And I'll be speaking a bit more about that when I cover GBS. We actually go to the other slide. It's an illustration of our pipeline in autoimmune diseases. So our ongoing studies include Guillain-Barré Syndrome, where we're currently in a Phase II/III potentially registrational program. Warm autoimmune hemolytic anemia is in the midst of a seamless Phase 0/Phase II program. And we'll be initiating multifocal motor neuropathy with 005, our intravenous drug candidate, as well as lupus nephritis with our subcu 009 drug candidate in the early part of next year. Our oral drug candidate hopefully should be in the clinic early next year as well, and that would be dedicated to autoimmune diseases. So Guillain-Barré Syndrome is our lead autoimmune disease. It's a devastating antibody-mediated disease which results in damage to peripheral nerves, triggering complement deposition and neurodegeneration. As seen in the schema, there are IgG and IgM autoantibodies to various nerve antigens, including gangliosides. And the GM1 ganglioside is something we'll reference later in the context of multifocal motor neuropathy. And this autoantibody-induced damage results in axonal and myelin dysfunction, and that results in neurological disability in these patients. So the premise here with respect to treatment with our Anti-C1q therapeutic is to mediate nerve injury acutely in these patients. And that should allow a faster and more complete recovery to baseline function. On the left here, we have evidence of target engagement with our Anti-C1q inhibitor, 005, which shows rapid and complete target engagement. This is with our functional assay CH50 assay. And also with our free C1q assay, we saw the same results, i.e., rapid and complete target engagement, in this case, for 3 weeks with our 75 milligram per kilo dose. In the middle, we have data on our NfL reduction, which occurred rapidly in these patients. NfL levels tend to be very high in GBS patients and have important prognostic significance. The higher one's NfL, generally the worse one does. So we were actually quite encouraged to see a reduction of NfL. And from a mechanistic point of view, it shows that we're reducing nerve injury due to autoantibodies. On the right, we have some efficacy data. This is a Phase Ib study, not dedicated to show efficacy in a powered manner. So therefore, we're encouraged to show an efficacy signal utilizing GBS-DS, which is a disability scale that's utilized for approval in GBS in both United States and Europe. And here, we have a responder analysis looking for really large functional improvements, and that's 3 points or more on the GBS-DS. And utilizing this high bar, we saw that 28% of patients treated with 005 met that bar versus 0 in the placebo. Just to give you an indication of the magnitude of this improvement, it's patients going from bed-bound to being able to walk independently. So we're quite encouraged by this data set, encouraged enough to initiate a Phase II/III study, which is ongoing and enrolling well. So in summary, proof of concept in GBS has increased confidence to expand into other autoantibody-immune diseases. 005 was well tolerated. We showed rapid and complete target engagement in both blood and CSF. We saw an early statistical decline of NfL, indicative of reduced autoantibody-induced nerve injury. And also, we had complete hemolysis inhibition, so actually the functional C1q assay that's shown in the prior slide was actually CH50. And so that gives us confidence with respect to inhibiting hemolysis in hemolytic anemias induced by autoantibodies such as warm and CAD. So transitioning to warm autoimmune hemolytic anemia, or wAIHA. So this in the midst of a Phase 0/II seamless design. wAIHA is a severe hemolytic anemia. The path to red blood cell hemolysis is actually quite heterogeneous in these patients. So we're utilizing a precision medicine approach, where we're enriching just for patients with classical complement pathway activity. That's in our Phase 0 study. And then we treat those targeted patients in our Phase II component. The Phase II component comprises 2 doses of 100 milligrams per kilo separated by a week. And that should give us complete target engagement for a 6- to 8-week time frame, during which we would look for changes in hemoglobin as well as changes in biomarkers of hemolysis. This slide highlights some of the data we've had by this enrichment approach. So on the left, we have some early data from our ongoing Phase 0 study, which shows that we're able to select patients based on their classic complement signature. Interestingly, those with classical complement pathway activity tended to have high degrees of hemolysis, as indicated by high levels of LDH. In the right graph, we have data from a preceding bio sample analysis from warm patients, where in about 1/3 of patients were able to show complement-activated antibodies, which are completely inhibited by 005. So I'm now going to move into our new autoimmune diseases that are mechanistically rated. Firstly, lupus nephritis. And this slide depicts the rationale to advance into this new indication. So firstly, this is really a terrible disease, enormous unmet need. And fortunately, we have Dr. Dooley will speak to this unmet need. Lupus nephritis is an autoantibody-mediated disease. And specifically, there is an autoantibody termed PACAs or, pathogenic Anti-C1q antibodies, which bind to the tail region of endogenous C1q, driving aberrant classical complement pathway activation, immune complex formation and disease activity in lupus nephritis patients. And so with our Anti-C1q therapeutic, in this case, 009, we're actually uniquely able to target and inhibit this PACA-induced pathology. Our antibodies block the head region of C1q and prevent the binding of PACA to tissues. Ted will speak a bit more about underlying mechanism of action of lupus nephritis. And so we have a unique precision medicine approach to identify specific patient subsets via assays for classical complement pathway activity. Then with respect to rationale to advance multifocal motor neuropathy. I've alluded to the mechanistic overlap with GBS. MMN is caused by Anti-GM1 IgM autoantibodies that activate the classical complement pathway, and in MMN model, and Dr. Hugh Willison will speak to this in more detail, Anti-C1q prevented nerve injury induced by anti-GM1 IgM antibodies from patient sera. This is sera from MMN patients. Ted referenced the Phase Ib data, where we were able to block anti-GM1 IgM activity in GBS patients with in vivo administration at 005. And then from a clinical development point of view, we're able to leverage existing relationships with key opinion leaders who look after GBS and MMN patients and our experience with clinical endpoints and disease understanding. So that should result in increased probability of success in multifocal motor neuropathy. So with that, it gives me great pleasure to introduce Professor Mary Anne Dooley, who's Professor of Medicine at the University of North Carolina Kidney Center. Dr. Dooley is an experienced rheumatologist with at least 30 years of experience, much of that dedicated to the care of lupus nephritis patients. Indeed, she runs a busy lupus nephritis clinic. And of note, she has been a key investigator in multiple lupus nephritis clinical trials over the years. So Dr. Dooley, I'll hand it over to you.

Thank you. So I have been involved in treatment of lupus and lupus nephritis patients for more about 30 years. And the patients typically are among the sickest patients available because they have not only a severe autoimmune disorder, but all the complications that come with renal disease. Lupus nephritis is the most severe complication of patients with lupus overall, and it can have chronic and severe life impacts for many of the patients. Overall, lupus nephritis affects about 130,000 people in the G7, at least half of whom are in the United States. Half of patients with lupus nephritis will develop lupus nephritis during the course of their disease. 80% of patients will develop this within the first 5 years of disease. In general, patients are young women. 85% of lupus nephritis patients are female, and they present most often during childbearing years. Children with lupus will eventually develop lupus nephritis 85% of the time. And the progression to end-stage renal disease can be severe. Depending upon the characteristics of the patients, 30% to 70% of patients will progress to kidney failure with a need for dialysis or transplantation over the course of their disease. This obviously has a significant personal and economic impact on patients, but also on Medicare expenses and on families of patients who have lupus nephritis. Next, please. The current standard of care for lupus nephritis is suboptimal, and that is for almost all of the clinical trials. The response rate at 6 months is between a maximum of 50% for patients who achieved both a complete and/or a partial remission. And as we'll see in a little while, the -- having a partial remission is an insufficient response. So patients typically will start with treatment for their lupus nephritis. And that often is high-dose steroids. If the disease is severe, they'll start with IV steroids in the hospital and then progress to all steroids with a tapering schedule over the first 3 to 6 months. This is associated often with increase in blood sugar, blood pressure and Cushingoid faces, where patients become a lot more swollen around the face and neck, which is very embarrassing for young patients. Along with this, there could be severe fatigue, weight gain, increased risk of cardiovascular events, and if not controlling the kidney disease rapidly, then progressive kidney damage and scarring. Patients who have renal disease have a decreased risk of fertility. But also if they are pregnant during active renal disease, they have significant pregnancy risks. Diagnosis of lupus nephritis is most often times done by use of kidney biopsy. Repeated biopsies may be done over the patient's lifetime to assess whether they are in an active or chronic stage and to what degree immunosuppressive therapy would be helpful. Patients then, after initial treatment with steroids, immunosuppressive therapy is added almost as quickly as possible. These drugs carry with them risk of side effects including infection, also long-term risk of malignancy. Patients not responding to immunosuppressive therapy will advance to biologic therapy. Now patients, about 50% of whom do not have a response to their initial regimen, may then be subject to go back through the same cycling, risking the same side effects. And repeated episodes of lupus nephritis are one of the biggest risks for ending up on dialysis because of loss of renal function. Patients with lupus do well with kidney transplantation. However, patients with the highest risk of lupus nephritis, often brown or black patients, are harder to match for donors and therefore mainly a longer period of time on dialysis. Patients with lupus on dialysis do as well as other lupus patients. However, the risk of death per year in patients with end-stage renal disease is 10%. So you have a young woman facing a risk of death at 10% per year on dialysis. Patients oftentimes have increased mortality in that setting infections, certainly depression and difficulty with expenses in terms of being difficult to work when you're spending 3 days a week in a dialysis 3 to 4 hours, required transportation and other care. Next slide, please. So overall, lupus nephritis negatively impacts survival. So up at the top, you have patients -- all patients with lupus and their mortality. If you take out any patients who had preexisting kidney disease, the risk is similar to the general population. However, when you begin to look at patients with renal disease, please click, you see that the standardized mortality ratio is much higher. Next slide please. And finally, patients who have progressed to end-stage renal disease have significantly higher mortality ratios. Next slide. Lupus nephritis confers the highest risk of mortality in patients with lupus. And this can be related to race or ethnicity, also to socioeconomic status. So patients with the highest risk of mortality are patients with African ancestry, lower down, patients with Hispanic ethnicity and then patients who are Caucasian have the lowest risk of end-stage renal disease. In addition, when you look at end-stage renal disease due to lupus nephritis, there is an impact of socioeconomic status with those at -- with low socioeconomic status at higher risk. However, it is also known that race trumps socioeconomic status, in that African ancestry patients have -- with a high socioeconomic status have very similar outcomes as patients with low socioeconomic status. Next slide, please. There is a significant need for improved treatments for lupus nephritis, both to preserve kidney function and improve long-term outcomes. We're very fortunate to have new drugs approved for treatment of lupus nephritis. But as yet, most do not provide a complete or partial remission greater than 50% within the first 6 months of patients who receive them. This is an analysis of an older trial in terms of looking at a 10-year course of survival of patients without end-stage real disease, and this is looking at a 10-year period of time. So if you achieve a complete remission, which would be your renal function remaining unchanged through the trial or in the normal range as well as having 500 milligrams or 0.50 gram of protein compared to 300 milligrams, which would be expected in a normal patient, that would equal a complete renal response. Now if you have a partial response, and typically, that means that your kidney function has remained within 25% of the start of the trial and that the protein that you're putting out, if it is in the lower range, must be less than 1 gram per day. If you have what is called nephrotic proteinuria, and that is you're putting out a very large amount of protein, typically more than 3.5 grams per day, then what you're looking at is patients who have to achieve half of the proteinuria but also be under 3 grams per day. So those are fairly lenient criteria in terms of saying that you've had a response and then it's a satisfactory response, but pretty generally used in trials as partial response. However, if all you achieve during treatment is a partial response, then you have a 60% chance of going to end-stage renal disease within 10 years. So what the goal should be is a complete renal response, not a complete partial response. And what we need is to get the majority of patients to a complete response quickly to avoid damage to their kidney tissue. If you do not respond to therapy, you have about a 90% chance of being on dialysis within 10 years. Next slide, please. The key takeaways are lupus nephritis is a severe, life-threatening manifestation of lupus. It is characterized by inflammation followed by fibrosis of the kidney, and it compromises kidney function. Repeated flares of lupus nephritis is the #1 cause of loss of renal function in lupus nephritis. The current standard of care and immunosuppressive therapies carry significant toxicities, but importantly, they fail to reduce the disease burden in more of half of patients who are treated. The quality of life and social economic burden of lupus nephritis is considerable for patients and their families, also for the country since Medicare pays for all dialysis. There is a significant unmet need for new treatments to further improve outcomes in lupus quickly, minimizing kidney damage, exposure to steroids or other immunosuppressive drugs and severe outcomes. Thank you.

Great. Thank you. Thank you, Dr. Dooley, for the great discussion on lupus nephritis. Lupus nephritis has been very difficult to approach from a drug development perspective, and I hope to impress upon you today how we're taking a really unique approach with unique therapeutic in this space. And I'll start by talking about the drug we're going to be going into lupus with. This is ANX009. This is the Fab fragment of 005 as a single -- as a Fab, it only has a single binding arm, but it retains the full high affinity as the whole antibody. So it's still less than 10 picomole against C1q. And when it -- when given subcutaneously, the drug is taken up into the circulation and it binds all of the C1q that's available. And because it has this high affinity, it remains bound to the drug. So as a Fab, the free drug is cleared from the circulation very quickly. But the drug bound to C1q remains bound until C1q is turned over. So a single dose can last for 4 days, which is a slide I'll be showing you in a moment. So we're developing this drug for hemolytic anemias because its activity is really limited to the blood space. And we're developing it for lupus nephritis so that we can address or protect the vascular filtration unit or the glomerulus of the kidney, so again, addressing the vascular space, the vascular component of this disease. Next slide. Let's -- sorry, I'm having technical -- okay. Here we go. There it is. So we completed our first in-human study with ANX009, so done in healthy volunteers. There were 6 different cohorts, single-ascending and multiple-ascending doses. There is a clear dose response. The drug was well tolerated at all dosing levels, and it maintained target engagement for a prolonged period of time. So shown here in the graph is dosing with a high dose every 3 to 4 days. And what we can see is a full target engagement of C1q and full C1q in suppression 4 days after the last dose. So this study taught us that we can use this drug twice weekly subcutaneous for treatment of -- in inhibiting C1q in the blood space. Next slide. Okay. So why see C1q in lupus nephritis? So lupus is, as Dr. Dooley explained, a disease driven by autoantibodies. These are antibodies against a number of different antigens, including a patient's own DNA. So when these antibodies bind to their antigen, for example, DNA, the antibodies bind, they activate the classical complement cascade. So C1q is there, C3 and C4 are deposited. And this forms an immune complex. And so this immune complex is in the circulation. They become trapped in tissues, particularly within the kidney. Now about 50% of SLE patients will develop the so-called pathogenic Anti-C1q antibodies or PACAs, which is how we refer to them, and Sanjay mentioned this before. These are antibodies that recognize bound C1q -- selectively bound C1q. And so they'll see these immune complexes of C1q in the kidney and they enhance C1q activity. So this can lead to a lot of focal and local tissue damage. About 90% of SLE patients with active lupus nephritis have these PACA antibodies. So it's very closely associated with disease, and we'll talk more about that in a minute. Next slide. So this is the way PACAs work. So again, C1q binds to immune complexes within the kidney. The PACAs then recognize the tail region of C1q. It's binding to the immune complexes via its head region, the PACAs recognize the bound C1q via the tail region. Of course, C1q is a major amplifier of antibody function. So these bound PACAs recruit more C1q, which recruits more PACAs. And then this leads to explosive complement activation within the kidney and a lot of local tissue damage. Now in the case of ANX009, it binds to the head region of C1q, so it prevents its binding to immune complexes and its accumulation in the kidney. It prevents PACAs from binding to the tail region of C1q, so basically shuts down this entire inflammatory cascade. This is really unique amongst complement inhibitors for addressing this specific mechanism, where C1q itself is functioning as an autoantigen in this disease. Next slide. Just to give an example in an animal model. This is a model caused by an autoantibody. And you can see on the left image there that there is some degree of complement activation or accumulation within the kidney. This is within glomerulus, the vascular filtration unit. So at baseline disease, there's a bit of complement activity. But when the animals are given PACAs intravenously, this activity really increases. You can see a lot of complement deposition on the glomerulus. And then on the right side, the graph shows that this corresponds with disease activity. So at baseline disease, there's very little protein in the urine, proteinuria as a measure of disease or kidney function. But then when PACAs are added, there's a great deal of protein in the urine. So that is usually greatly exacerbated. The next slide. So that was in animal models. But in patient studies, as Sanjay said, we have a collaboration with Maria Dall'Era from UCSF. And she provided us with very well-annotated clinical samples from 3 different groups of patients: healthy controls, patients with quiescent lupus nephritis and then patients with active lupus nephritis. And we measured levels of these pathogenic C1q antibodies, these PACAs in the serum. And we found that they were very highly enriched in patients with active lupus nephritis. In fact, looking at the right graph, the level of PACAs in patient sera correspond very strongly with complement activation markers. So the more PACAs, the more complement activation was happening in these patients. The next slide shows that the more complement activity, the more protein in the urine. So PACAs and complement activity are closely correlated with the level of active disease or proteineuria. And so by looking at these complement activation markers, we'll be able to identify patients that are most likely to respond to ANX009 in our Phase Ib study. Next slide. So just in summary, C1q itself is a unique autoantigen in lupus nephritis identified by these pathogenic antibodies. These PACAs are associated with increased complement activity and disease activity in patients. So there's a real strong therapeutic rationale for targeting C1q. It's unique amongst complement inhibitors in its ability to block C1q binding. ANX009 specifically targets the vascular aspects of lupus nephritis because it's limited to the blood space and it will be blocking C1q binding to these immune complexes. And as I said, we've taken this into our first-in-human study, and it was very well tolerated and fully inhibited C1q. So with that, I'm going to turn this over to Dr. Keswani again to discuss our clinical plan in lupus nephritis. Thank you.

Great. Thank you, Ted. So this slide really is an overview of our translational approach in lupus nephritis. So starting out with well clinically annotated bio samples from lupus nephritis patients with varying disease severity, and really having the confidence that we can enrich for 4 patients with a high degree of complement activation and, also of note, a high degree of disease activity as well. And so we'll be initiating a Phase Ib study in the early part of next year, which essentially will be a proof-of-biology study. And in this study, we'll enrich the patients with this classical complement pathway activity and evaluate whether we can normalize this activity in this study. And that would set us up for later phase trials, which we properly powered efficacy studies, again, in this targeted patient subset. This is a high level overview of our Phase Ib proof of biology trial in lupus nephritis. It's an open-label 1-month study with run-in and follow-up periods. The patients who would be enrolled in this study would have Smoldering disease. So they have active lupus nephritis but not be in an acute lupus nephritis flare. And as Dr. Dooley articulated, many patients do not have complete remission and continue to have progressive renal dysfunction and significant levels of proteinuria. And so these are patients that were approved into this study with protein level of more than 500 milligrams per day. They would also have this classical complement signature that we've alluded to. Because they're not in an acute flare, we expect them to be on stable background therapy for this relatively short study. In terms of key objectives, safety and tolerability are obviously key, and we'll be looking to normalize their complement signature in this study. And we have confidence that we can rapidly do this with our Anti-C1q therapeutic. We'd also look at markers of renal tissue damage and function in this study, including sensitive measures for proteinuria, utilizing [ perm ] selectivity. And as mentioned, the plan is to initiate in the early part of next year. So we're now going to switch gears to multifocal motor neuropathy. And it gives me a great pleasure to introduce Professor Hugh Willison, who's President of Neurology at the University of Glasgow and is NHS Trust Director of the Diagnostic Neuroimmunology Laboratory at the Southern General Hospital. Dr. Willison has enormous expertise in both the clinical and research aspects of peripheral nerve disorders, including GBS, MMN, CIDP and a whole host of other peripheral nerve diseases. So I'll hand it over to you, Dr. Willison.

Thank you very much, Sanjay, for that introduction. As Sanjay says, I spent the whole of my professional life working in this disease area of autoimmune neuromuscular disease, most notably in Guillain-Barré Syndrome and multifocal motor neuropathy, in which this molecule that you've heard about, GM1, is the target for autoantibodies that drive the pathology in these syndromes. Next slide, please. So what we're going to cover today is a few brief remarks on the evidence that there's a pathogenic role for Anti-GM1 complement fixing antibodies in this disease category, multifocal motor neuropathy, and talk a little bit about the disease. The parallel syndrome, Guillain-Barré Syndrome, as you've heard, is also associated with a slightly different type of Anti-GM1 antibody of a different class and duration. And that is in -- currently in clinical trial with ANX005. We're going to talk a little bit about animal models and the role of C1q and a little bit about the unmet clinical need in this multifocal neuropathy disease category. The next slide, please. So one of the first things to think about is, well, what is multifocal motor neuropathy? It's a progressive paralytic disorder which goes on for decades in many patients with this characteristic clinical phenotype that you can see in the wee picture there of wasting and paralysis of the upper limbs. And this accelerates and progresses over time, as I say, often over decades. One of the common immunological features in these patients is the presence of this Anti-GM1 IgM antibody, which is believed to be the causal factor that underlies the electrophysiological conduction block that you see in these patients. And it's these 2 factors which help to make the diagnosis. It's a rare disorder. We estimate somewhere in the region of 12,000 patients in the U.S. and the EU at any one time. But it is a chronic lifelong disease, often affecting people in quite young middle age. And therefore, one is committing, in the absence of curative treatment, ongoing therapy possibly lasting decades. The standard of care is a single drug. There is only one current therapy for it, and that's intravenous immunoglobulin. Despite being on intravenous immunoglobulin, patients do still progress over time. Some patients are resistant to treatment with IVIg and other patients are unable to tolerate IVIg treatment. There are also potentially issues with long-term IVIg availability. It's a blood product made from human donor material, and this raises all kinds of potential safety and biosafety and side effect issues that may arise. And apart from IVIg, nothing else has been shown to be effective treatment in multifocal motor neuropathy. Next slide, please. You've seen a picture a little bit like this before. This is a picture of a nerve, of a peripheral nerve, the nerves that run through the arms and the legs. And they're decorated with this sugar molecule which sits on the surface called GM1. And the antibodies in both Guillain-Barré Syndrome and multifocal motor neuropathy bind to GM1 on the nerve surface, and through that, initiate the complement cascade. And IgM, in particular, is a very potent vector of C1q and a very strong driver of the initiation of the classical cascade complement pathway. So the idea is that in multifocal motor neuropathy, the IgM antibodies bind onto the surface of the nerve. They then fix C1q, and that initiates complement activation with all the downstream consequences of that immune cell recruitment and membrane complex formation, et cetera. The next slide, please. And we know from clinical material that the amount of anti-GM1 antibody, this is in the left-hand panel here, correlates very well with the amount of complement that can be activated in an in vitro assay. And if we look at the right-hand panel there, we can also see that the amount of weakness, the clinical readout of this disease, also relates to the extent of complement deposition in model systems. Next slide, please. Similarly, we know that the serum of these patients with MMN activates the complement pathway, and that if one looks at this in C1q deficiency states, that the amount of complement activation is very substantially reduced. And if we look at the right-hand panel, we can see this bright -- this nerve network in a motoneuron in vitro model of multifocal motor neuropathy becomes very richly decorated by multifocal motor neuropathy sera with activation of complement. And the consequences of this is that holes get punched in the nerve plasma membrane and allow in calcium fluxes, which are very, very neurotoxic indeed. And it's this pathway which is involved in the progression of pathology in multifocal motor neuropathy, which, of course, we don't see under normal control circumstances. Next slide, please. Ted showed you this slide before. And it's repeated to reinforce that the anti-GM1 antibodies in multifocal motor neuropathy and in anti-GM1 antibodies in Guillain-Barré Syndrome can affect the proximal part of the nerve routes where they exit the spinal fluid and that the ANX005 is able to penetrate this site within the cerebrospinal fluid. Next slide, please. One of the reasons to be very interested in multifocal motor neuropathy is because of the progress that's being made with ANX005 in Guillain-Barré Syndrome. Whilst Guillain-Barré Syndrome is, in acute phase, highly aggressive, fulminant onset paralytic neuropathy, the sort of tsunami of peripheral neuropathies, as it were; multifocal motor neuropathy is a slow flood occurring over many years. But many of the basic pathological features are the same. And that is the presence of these anti-GM1 antibodies that are driving the disease, principally IgG, in the case of Guillain-Barré syndrome; and IgM, in the case of multifocal motor neuropathy, but both of which binds C1q and therefore drive the complement network and the pathological features of conduction block. And axonal degeneration and muscle weakness are common to both these conditions. And many of us who work in clinical neurological practice have worked in networks in which we see patients with multifocal motor neuropathy and Guillain-Barré Syndrome and thus have ready access to expertise in these particular areas and have developed a lot of rating scales and assessment methodologies for looking at these disorders. Next slide, please. One of the areas of work which has progressed extremely well in multifocal motor neuropathy has been the deriving clinical scales for measuring endpoints and outcome and progression of the disease using various different muscle strength measurements using quantitative dynamometry using observer rating scales and patient self-reported rating scales. And one can also monitor, to some extent, the progress of the disease through serial electrophysiology. And so the clinical endpoints that would be used in the clinical trial are well established and varied, which gives a clear idea that an outcome could be established in a trial of Anti-C1q. The next slide, please. So just to summarize what I've said, multifocal motor neuropathy is a very slow burn but nevertheless devastating IgM autoantibody complement-mediated disease with a very high unmet need and with certain similarities to the pathology in Guillain-Barré Syndrome. We know that C1q is involved in models of multifocal motor neuropathy, in which we know on blocking C1q, that we have an effective aggregation of the disease. We know through a shared experience with Guillain-Barré Syndrome that multifocal motor neuropathy contains sufficient similarities to also be a promising indication. Ted and Sanjay and Doug have talked a lot about the fact that the advantage of C1q inhibition is this is right in front of the complement pathway, at the sort of critical part in it, and therefore, may be a particularly effective point at which to lock it in these neuromuscular diseases. And finally, around the world, there are neuromuscular centers that have the experience in patient cohorts to be able to deliver clinical studies in this area. And hopefully, take those through, if successful, through to regulatory approval and standard of care, clinical use. And I think that concludes my slides. So thank you very much for listening.

Thank you, Dr. Willison, for a really terrific and informative presentation. So I'm now going to give a high-level overview of our proposed Phase II trial of 005 in multifocal motor neuropathy, which should initiate in the early part of next year. Now of note, the protocol hasn't been finalized yet, pending discussions with our key collaborators and investigators. The trial design is a randomized double-blind trial assessing efficacy of 005 versus IVIg. And in this case, IVIg rescue would be provided, and that allows the trial to be feasible and also informs an important objective here, which is the need for IVIg retreatment. In terms of the target patient, these patients would have early multifocal motor neuropathy with some reversibility of their conduction block and a documented response to IVIg. And we actually assess their response to IVIg in the run-in periods for these patients. Now one of the advantages about MMN in terms of clinical venue is that there are established clinical endpoints that Dr. Willison has alluded to and also an established regulatory path. Key objectives for this Phase II trial would be safety and tolerability, strength of predefined muscle groups and grip strength by hand dynamometry. As Dr. Willison mentioned, the hands are -- particularly, effective hand function is affected. Indeed, we'll likely use a 9-hole peg test and other functional tests, accessing the upper extremities in this study. So with that, I think we're now going to transition to Q&A.

And your first question will come from the line of Phil Nadeau.

A couple of questions on the trials that have been defined this morning. First, on 009 Phase Ib in lupus nephritis. You mentioned one of the goals of that study will be the confirmation of therapeutic effect. Can you give us some sense of what you would consider such a confirmation of therapeutic effect? What type of changes on which biomarkers or which clinical end points?

Yes. So we'll essentially look at complement activity, specifically classical complement activity in these patients both at baseline and the run-in period as well as post dose. So that will be the primary goal of the study, to normalize their complement signature in that 1-month study. Now in an exploratory fashion, we will look at measures -- more established measures of renal function, such as proteinuria, UPCR, eGFR, et cetera. But these will be exploratory because of the short duration of the study.

Got it. Okay. The second question, on the 005 Phase II in MMN that you just discussed. I apologize if I missed it. Did you say the duration of the study, and the second part of this -- the question is, given that's head-to-head versus IVIg, what impact would you expect IVIg to have an MRC strength or grip strength over the duration of the trial? Kind of what is the hurdle that IVIg is likely to set for 005 in that trial?

Yes. So the first thing is that we're -- we haven't finalized the protocol yet. But just to give one an idea. Typically, the treatment period utilized to assess efficacy is a 12- to 16-week treatment period. So in this time frame, one would expect actually a decline of patients with respect to natural history data in terms of some key endpoints like grip strength and the MRC score that you mentioned earlier. These patients would be IVIg-dependent, and so IVIG typically prevents some of that decline in these patients. And so we would be looking at our efficacy versus IVIg prevention of decline in this study.

And your next question will come from the line of Anupam Rama.

And just a quick question for the KOL on GBS. You talked about the disease overlap overall. But with the known data for GBS, biomarker and some of the functional data, what gives you confidence in pursuing the disease here based on what you know on the data side on GBS? And then what would you place as a minimal threshold as a proof of concept for the initial study in MMN?

Sanjay, are you looking for me to address that?

Yes. I think he directed the question at the KOLs.

Yes. I mean, I'm happy to give it a thought.

Yes. sure.

And thank you. It's quite a complicated question, of course, that you asked. And clearly, when one does a sort of deep, micro dissected analysis of Guillain-Barré Syndrome and multifocal motor neuropathy, one can see very clear differences. However, at a higher level, the presence of both demyelination and axonal degeneration, the presence of relevant autoantibody, the particular predilection for affecting motor nerves in particular types of GBS, all rather suggest that they are mechanistically linked even if at a rather high level. And so I think that a successful study in GBS should be a reasonably positive starting point to consider similar diseases. And I don't think one would necessarily restrict that to multifocal motor neuropathy. As you know, there's also a chronic form of Guillain-Barré Syndrome that we call CDIP, chronic inflammatory demyelinating polyneuropathy, which also has certain similarities. So I think the expression used in the presentation was a gateway or a trailhead into it. And I think that's the best word that I would describe my answer to your question.

And your next question comes from the line of Tazeen Ahmad.

A couple from me. Maybe referencing a slide that you presented as part of your deck. When you think about how best to formulate therapy, for some of your therapies, you're choosing to choose -- to do a subcu injection. And for others that you might pursue, you've talked about taking an oral approach. So my question is how are you determining what's the best route of administration for therapy? And how does the indication kind of play into that? And then secondly, for wAIHA. As it relates to time lines for data, can you just remind us when we should expect to see the next round of wAIHA data and what you would consider to be clinically meaningful?

Do you want to start with that, Sanjay? Yes, with regards to...

Yes. So in terms of -- go ahead, sorry.

No, go ahead, Sanjay.

Yes. So I think the first question related to drug candidates -- choice of drug candidates, so for our intravenous drug candidate, 005, we have shown that we get CSF penetration. So I think the diseases where we would want both blood and CSF tissue distribution, that would be the choice of therapeutic. We actually do have a follow-on antibody, 105, which is also intravenous, which potentially may have superior dosing characteristics to 005. So for example, in GBS, we do think CSF penetration is important because nerve routes are important site of pathology, and having CSF target engagement, we think, will be extremely helpful. And indeed, in our particular case, it was interesting at the doses that we saw good CSF penetration had NfL reduction. And in dose -- low doses where we didn't see that, we didn't see NfL reduction. In multifocal motor neuropathy, that's likely also the case in terms of just ensuring that the nerve routes are covered. In diseases which are vascular, like hemolytic anemias or organs that are affected that are highly vascular such as the kidney, the subcu route, specifically by the Fab fragment, is a preferential formulation or route of administration. Now clearly, an oral drug would be potentially game-changing in many of these diseases, particularly if there is a broad tissue distribution. So currently, we're proceeding to an IND or IND-equivalent towards the end of this year. But I think we'll have many choices in terms of indications to get to the clinic in the early part of next year. So anyway, I don't know if Ted and Doug, you want to expand more on that drug candidate selection.

No, I think that's a good description, Sanjay, particularly for where we are today. Once we get the oral in hand and have really characterized its properties, we'll then make determinations about what indications to take into. But as you said, Sanjay, we think it's got broad applicability across a range of autoimmune diseases. And so whether we take that into later Phase III trials, in some of the indications that we've already initiated, as well as newer indications, we'll make that determination once we finally characterize that drug candidate, hopefully later this year. And then your second question, Tazeen, was just with regard to timing on the warm autoimmune hemolytic program. And we are still guiding towards early 2022 for data in that program. I will say that the Phase 0 component of it, the screening component which we showed some data this morning, is going quite well. It's an open-label study. So we will, at some point in time, hopefully have a sufficient number of patients in the Phase II program to make a determination if we can release data earlier than what we've guided. But right now, we're staying with early 2022.

Okay. And I guess, what would you consider to be clinically meaningful results at the readout?

Sanjay?

Sure. So we're looking at hemoglobin changes, specifically hemoglobin changes of more than 2 grams per decoliter as meaningful, similar to the bar that others have set in the context of hemolytic anemias. But also we'll be looking at reduction in biomarkers in hemolysis, including serum LDH, haptoglobin and bilirubin.

[Operator Instructions] We have no other questions in queue. I would like to turn the call back over to management for closing comments.

Thank you so much. Well, thank all of you for joining us this morning. Really excited about this autoimmune approach that we are taking and expanding into additional indications. We see significant opportunity across the entire portfolio and specifically in the autoimmune space. Indeed, 24 million Americans suffer for antibody-mediated autoimmune diseases, many of which for which there is inadequate therapies. And we've built a foundation here at Annexon where we're able to target those. We're doing so in a very rigorous, intentional fashion, and we look forward to continuing to produce data in the space and assess additional indications to pursue as we advance. And with that, I will close with our last slide, just really summarizing where we are with Annexon today. Very well positioned with what we know based on our platform technology today and where we're going. Again, C1q is uniquely differentiated, initiating the entire cascade, and so we think has brought applicability from an efficacy and a safety perspective in stopping downstream aberrant activity in a host of diseases. The foundation has been laid. We understand how to engage the target across the body, brain and eye with multiple drug candidates. And we're well poised with 7 mid- to late-stage clinical trials underway to produce significant data readouts for patients and investors over the next 2 years. And the team is frankly praying with their hearts and minds. These are diseases that are devastating. We know many patients in these different diseases. We have family members impacted by many of these diseases. And so we're quite intentional and quite focused in making a difference in the lives of folks who are suffering from them as well as, again, creating value for those who support us along the way. So we thank you for your attention this morning. We certainly are available to connect with you after today's call if there are additional questions. And we wish you all the best. Thank you.

This does conclude today's call. Thank you for your participation. You may now disconnect your line.