Arrowhead Pharmaceuticals, Inc. (ARWR) Earnings Call Transcript & Summary

Good afternoon, and welcome to the Arrowhead Pharmaceuticals KOL event. [Operator Instructions] As a reminder, this event is being recorded, and a replay will be made available on the Arrowhead Pharmaceuticals website following the conclusion of the formal presentation. I would now like to turn the call over to Vince Anzalone, Vice President of Investor Relations at Arrowhead. Please go ahead, Vince.

Thank you, Sarah, and thanks, everybody, for joining us today. Go ahead and click forward, please. So just to remind you all, we will be making forward-looking statements on today's call. So please refer to our SEC filings for risk factors. Next slide, please. So we've got a really good event today. We've got a great panel from external. Outside of the company, we have Dr. Richard Glassock, from the David Geffen School of Medicine at UCLA. And we also have Dr. Peter Browett, from the University of Auckland School of Medicine. From the company, we have our Senior Vice President of Discovery and Translational Medicine; Dr. James Hamilton; myself; Dr. Hamid Moradi, who is an Associate Medical Director; And then we also have Dr. Javier San Martin, our Chief Medical Officer, who will be available during the Q&A session. Next slide, please. So here's the basic agenda today. So we want to talk about our newest or most recently disclosed candidate, ARO-C3, which is targeting complement C3 for various nephrology and hematology diseases. Dr. Moradi, will then talk about the complement cascade generally and the biology of the complement cascade. Dr. Glassock will then talk about different areas in nephrology that may be addressed with ARO-C3 and then Dr. Browett will talk about the hematology options. Dr. Hamilton will then talk about some of our preclinical data and our general plans for the clinical program. I'll give a brief wrap-up, and then we'll open up the panel -- open up the call to Q&A from the panel. Next slide, please. One more forward. Okay. So just for those who may not be as familiar with Arrowhead. We are an RNAi therapeutics platform company. We've got a broad pipeline, now 10 clinical stage programs, 4 of those are partnered, 6 are wholly owned. We've got a good broad mix of early, mid- and later-stage programs, and also a good mix in our pipeline of targeting diseases that are rare and those with high prevalence. We also intend to grow our pipeline pretty aggressively over the coming years, and we hope to have 2 to 3 new clinical programs every year. All of these programs are built on a proprietary platform called targeted RNAi molecules or TRiM. I'll talk about that very briefly on the next slide. And we think that we have the potential for best-in-class delivery for liver-expressed proteins. And we also -- one big differentiator for us is that we think that we are capable of fulfilling the promise of bringing RNAi to tissues outside the liver. And lastly, we've got financial resources with a strong balance sheet to push our programs towards and into commercialization and also access to nondilutive capital through our partnerships with Janssen, Amgen, Takeda and Horizon. Next slide, please. So this is targeted RNAi molecules or TRiM. And basically, these are structurally simple sRNA conjugates that include targeting ligands that give us preferential uptake to our cell types of interest, linker chemistries that are optimized for each specific use, stabilization chemistries on the backbone of the double-stranded RNA to increase stability and an activity and duration. And then for some of our extrahepatic uses, we also have some structures that enhance PK. So for all of these together, all of these different features of the molecule are designed to optimize 4 different things, activity, specificity, versatility and then simplicity. And also, the ARO-C3 program we're talking about today is built on a clinically validated structure that we've used for multiple clinical programs for other liver expressed proteins and the same system has been in thousands of patients. So we're very confident in the translation of our preclinical results into human results. Next slide, please. Okay. So for ARO-C3. We see this as really having broad application across 2 different therapeutic areas. One is nephrology, and that's represented on the left side, both those 4 columns here. The right side is the hematology applications. And we -- with the way -- when we look at new targets, we tend to look at them for -- as having attractive characteristics across the different range of measures. And on the left side, the left column, is some of those measures that we use. Specifically, we look at the size of the patient population, both in the U.S. and abroad. We look at estimates of what the market believes that revenues will be over the coming years. We look at what the standard -- current standard of care is. Pricing, whether it's premium pricing or standard pricing and what the level of unmet need is. And we've said this a lot, but we're not looking to develop incremental me-too drugs. We want to bring drugs and that really have an opportunity to change the paradigm and fill substantial unmet need. Next, we look at the scale and the size of these development programs. We look at the clinical program, whether it would include a comparator or not, whether we know what the anticipated clinical endpoints are going to be and then a general idea about the development time frames. So I'm not going to go into all of these areas specifically. But if you look at the columns that are outlined in red, these are the areas for ARO-C3 that we're going to be focusing on initially. Specifically, the first column on the left is IgA nephropathy, the second nephrology area that we're going to be looking at is C3 glomerulopathy. And then on the right side, the hematology is PNH. And both Dr. Glassock and Browett will talk about all 3 of those areas shortly. Next slide, please. So now I'll turn the call over to Dr. Moradi, who's going to talk about the complement cascade in general.

Thank you, Vince, and good day, everyone. My name is Hamid Moradi, and I'm an Associate Medical Director at Arrowhead Pharmaceutical. And I'm going to provide a brief overview of the complement cascade and how C3 as a target for therapy may be of interest. Please go to the next slide. So as you may all know, innate and adaptive immunity are 2 major components of the immune system. Adaptive immunity involves antigen-specific responses that are highly adapted to each pathogen. It requires antigen receptors that bind to antigen as displayed in major histocompatibility complex molecules on antigen presenting cells. It is also called acquired immunity because it takes time for it to develop. It's not fast or rapid in action. But once formed, you have immunologic memory if you can go to next. And that's one of the hallmarks of adaptive immune system and that if reexposure to the same pathogen is associated with a more rapid and robust response. There are 2 components of adaptive immunity and that those are cellular and humoral components. The cellular components involves B cells and T cells and the humoral component involves antibodies that are produced by plasma cells. Now innate immunity on the other side is evolutionarily conserved, it's rapid, it's nonspecific. And it involves inflammatory responses to pattern-recognition receptors. And so it's not specific the way adaptive immunity is. Innate immunity is also made up of a cellular component, which are macrophages, mast cells, neutrophils and humoral component. Next, which is complement proteins. And if you go to the next slide. So the complement cascade is a crucial part of the innate immune system. And some of the main functions of the complement system are orchestration of opsonization and opsonization is simply just tagging cells or whether it's bacterial cells or apoptotic cells tagging them or marking them for destruction. Complement system also facilitates cytotoxic destruction through formulation of the membrane attack complex and there is also release of peptides, pro-inflammatory peptides that promote the inflammatory response. There are 3 pathways for activation of the complement system. And these 3 pathways are alternative, classical and lectin pathways. But as you can see on the picture on the right, regardless of the mechanism that the pathways are activated or the complement system is activated, all 3 converge on formation of C3 convertase, the enzyme that -- whose activation is required for the effector functions that we just spoke about. So if we go to the next slide. You see that the complement system is fairly complex and a detailed discussion about all the different components is beyond the scope of this presentation. And so for the sake of this presentation, we're going to focus on 2 of the major proteins in the complement system. And these happen to be the 2 proteins who have target -- who have been targeted for therapy and those drugs are approved and are used in conditions marked by aberrant activity of the complement system or overactivity of the complement system. So if we were to take a simplistic view of this system on how it works, if you go to the next slide. As I mentioned, you have 3 different pathways for activating the complement system, but all 3 converge on formation of C3 convertase. And what C3 convertase does, it catalyzes the enzymatic cleavage of C3 to C3a and C3b. C3b is an opsonization and again, it tags things for destruction. C3a is a pro-inflammatory molecule or peptide. But C3b is also a key component of C5 convertase. So in order to form C5 convertase, you need C3b. And once C5 convertase is formed, it converts or catalyzes the conversion of C5 to C5a and C5b. C5a again, much like C3a is a pro-inflammatory peptide, and C5b goes on to associate with C6, C7, C8 and C9 to form membrane attack complex, which forms pores on cells and destroys them. So C5 inhibitors are effective in preventing aberrant activity of the complement cascade by blocking the interaction of C5 with C5 convertase thereby blocking production of C5a and C5b which blocks formation of [ MAC ]. But as you can see, click one next, just once. And as you can see through C5 inhibition, you still leave behind the more proximal components, C3b and C3a. And so you may have still some residual disease in these conditions because C3a is still intact and C3b is being produced, so opsonization and the pro-inflammatory actions of C3a are still in play. So if we go to the next set of -- yes, whereas if you use a C3 inhibitor or if you knock down C3 in hepatocytes because that's where the majority of C3 is made, you block formation of C3b and C3a. And because C3b is a key component of C5 convertase, you indirectly also block the terminal complement pathway and formation of C5a and C5b which goes on to form [ MAC ]. So this is kind of the idea of why targeting the proximal pathway of complement might be more effective in these conditions that are marked by aberrant complement activity or overactivity of the complement system. And so if you go to the next slide. We know that everyone knows that there are currently C5 inhibitors in the market. And as I mentioned before, they don't impact the more proximal components of C3. And so if -- click next. There's been always this question of whether it's more effective to inhibit the proximal pathway of the complement system by inhibition of C3. And if we go to the next slide, this was actually pursued more recently, if we go to the next slide. Using a C3 inhibitor and comparing it directly in a head-to-head trial with C5 inhibitor in a patient population that is affected by aberrant complement activity. These are patients with paroxysmal nocturnal hemoglobinuria. And in this trial that was just published within the past year, C3 inhibition was compared to C5 inhibition. If you go next, as you can see, as pointed out in this -- in the design of the trial, and these patients were then followed. And if you click next. In the conclusion of this study, it was found that C3 inhibition was superior to C5 inhibition in improving hemoglobin and clinical and hematologic outcomes in patients with PNH, again, because more proximal inhibition of the complement pathway will catch those elements that are not caught by C5 inhibition, mainly C3b and C3a. And so you may ask -- if we go to the -- just one quick next. You may ask, what's the advantage of an RNAi system [ and hold right here? ] So how does the RNAi technology fit into all this? So for now, the C5 inhibitors. There are 2 of them that are FDA approved and both require IV infusion every 2 weeks or every 2 months. So the patients would have to go to an infusion center and have an IV placed. The infusion of these drugs will take 2 to 3 hours. And aside from the inconvenience, they only block the terminal complement pathway and many of the proximal complement actions, mainly C3b and C3a remain intact. So if you go next, one quick add. So the C3 inhibitor, which was shown to be superior in the recent trial is also FDA approved. However, that drug requires 20 ml of drug subcutaneously infused over 1 hour every 2 to 3 days. And as you know, many of these conditions that are marked by aberrant complement activity require long-term therapy. In the case of PNH, those patients require lifelong therapy, and this could be a challenge. There is quite a bit of drug infused every 2 to 3 days subcutaneously. But if you compare, click next, an RNAi approach, for example, ARO-C3, you can administer 1 ml of drug subcu every 3 to 6 months. And if you were to put this in pictures, you see that on one side, you have administration of 20 mls of drug subcutaneously every 3 days versus 1 ml subcutaneously every 6 months. So there could be significant advantages of an RNAi technology in this space over what's currently available. Now the conditions that we're looking to study our conditions where complement system plays a pathogenic role in pathogenesis disease, and these include paroxysmal nocturnal hemoglobinuria and also C3 glomerulopathy. And also conditions where complement -- aberrant activity of the complement system contributes to pathogenesis disease, disease progression and disease activity, and this would include IgA nephropathy. And so to talk about the latter 2 conditions, it is an honor for me to introduce Dr. Richard Glassock who is a world renewed nephrologist. He's a household name in the nephrology community and requires no introduction. Suffice it to say he's an expert in kidney disease and especially in glomerular diseases and many of the nephrologists in the U.S. are trained in management and diagnosis of glomerular disease based on his teaching and his publication. So it is my pleasure, Dr. Glassock to turn the presentation over to you.

Well, thanks very much, Hamid for your excellent presentation, your very nice introduction. As Vince said, I am a member of the faculty at the Geffen School of Medicine and I have devoted the bulk of my professional career to studies of immunological kidney disease and their treatment, including clinical trials. Next slide, please. Now I've been asked to introduce the subject of the complement system in kidney disease with specific emphasis on IgA nephropathy and C3 glomerulopathy. So I'll try in the next number of slides to introduce the topic to give an overview of these diseases and how complement might have a beneficial effect on their natural history. Next slide. I'm not going to go over the complement cascade again because of the beautiful presentation from Hamid, but I want to emphasize the central role of C3 in the genesis of the activation of complement in the glomerular diseases, which I'll be talking about. Next slide. Of course, complement is a very complex cascade, and all 3 of the major pathways of complement activation, the classical lectin and the alternative pathway, have been demonstrated to play important roles in the pathogenesis of a wide variety of glomerular diseases, but the extent that these pathways are activated and their relationship to disease differs in a disease-specific manner. Next slide. In IgA nephropathy, which we'll cover first. Next slide, we first must emphasize that unlike some of the other diseases we talk about, IgA nephropathy is a very, very common disease. In fact, it is regarded as the commonest form of so-called primary glomerulonephritis in the world. It requires a kidney biopsy to diagnose. At this moment in time, there's no reliable noninvasive diagnostic tests. And epidemiologic studies have indicated that there are about 14 to 50 cases diagnosed per million population per year, the highest in Asia, and the lowest in Africa. And the identification of IgA nephropathy, which requires a biopsy is greatly facilitated in countries that have routine urinalysis screening because that leads to more biopsies and more kidney biopsies leads to more identification of IgA nephropathy. Next slide. Now IgA nephropathy can present clinically in a variety of different ways. The commonest way is with the development of hematuria that is blood in the urine, which could either be persistent or episodic and can be visible or nonvisible or microscopic or visible also called [ gross ] or microscopic hematuria. This hematuria in IgA nephropathy is often accompanied by proteinuria often without any symptoms. But there are a variety of other syndromes or clinical presentations that can characterize IgA nephropathy. These are relatively uncommon, accounting for less than 10% of the total population. So patients with IgA nephropathy present to their physician usually with hematuria with or without proteinuria. Next slide. The commonest presentation is hematuria and proteinuria without any symptoms, without any systemic involvement like joint pain or rashes or other systemic manifestations. This tends to present as a kidney limited disease. Next slide. However, the pathology underlying this form of kidney disease, IgA nephropathy, is very heterogeneous. Here are 6 slides taken from biopsies of patients with IgA nephropathy, showing a variety of different histopathologic form ranging from barely different from normal to proliferative forms of glomerulonephritis seen in the upper 2 panels on the right and including a very destructive form of glomerulonephritis known as crescentic GN. Fortunately, this is an uncommon presentation of IgA nephropathy. Next slide. Despite this histological heterogeneity the immunohistochemistry, the immunologic appearance of this disease under the immunofluorescence microscope is quite uniform showing deposits of the IgA protein, a serum protein, along with its antibody and complement in the mesangial or supporting structure of the glomerular capillary walls. Next slide. Fortunately, we have a great deal of knowledge about the pathogenesis of this lesion, developed largely from the laboratory of Jan Novak at the University of Alabama and Birmingham and laboratory in Japan led by Suzuki and other investigators. It is regarded that this disease develops as a consequence of 4 steps. The first step is an increase in the production and appearance of a form of IgA protein, which is galactose deficient. This is an abnormal form of IgA itself. These galactose deficient IgA molecules are produced because of a genetic predisposition and because of an abnormality in the trafficking of the B cells that produce them from mucosal, either intestinal or respiratory to systemic sites. The second step is the production of antibodies, autoantibodies to these abnormal galactose deficient IgA molecules, thus forming immune complexes in the circulation. Now some of these molecules can actually form immune complexes [ inside you ]. But the important aspect of the formation or deposition of immune complexes is that once they localize in the kidney, particularly in the glomerular, they've set off a cascade of inflammatory processes prominent among which is complement activation and the activation of complement along with other events, produces the morphologic changes in the kidney that are illustrated and the clinical features of hematuria and proteinuria. Therefore, IgA nephropathy can be attacked therapeutically by directing one's attention to any of the 4 complements, but the last of these allows a broad approach to the treatment of IgA nephropathy. Next slide. Now the amount of proteinuria that patients with IgA nephropathy, excrete in their urine has a very marked effect on prognosis, which means you can identify patients who have a favorable long-term prognosis or an unfavorable long-term prognosis by measuring protein in the urine. And a reduction in the level of protein in the urine has been associated with an improvement in the prognosis of IgA nephropathy, and it represents a surrogate outcome measure in clinical trials of therapy of IgA nephropathy, perhaps the best of the surrogate markers of outcome. Next slide. We now have a very powerful tool to predict in advance the outcome of any given patient with IgA nephropathy by combining clinical and pathological parameters. And when this tool is applied to patients with or without ethnicity and race, one can identify patients with a very benign outcome, low-risk patient with a 5-year risk of kidney failure of around 1% or 2% to patients at the highest risk with almost a 50% risk of developing kidney failure and the need for dialysis and transplantation within 5 years. This powerful tool allows identification of candidates for clinical trials which -- in which one can measure outcomes over reasonable time periods, 1, 2 or 3 years. Next slide. Now the conventional treatment of IgA nephropathy at the present time is renin-angiotensin system inhibitors either converting enzyme inhibitors, angiotensin receptor blockers or direct renin inhibitors, and this is a standard of care approach. These drugs are used because they lower proteinuria and improve the prognosis. Very recently, within the last year, sodium-glucose cotransporter-2 inhibitors, the so-called flozins and in particular, dapagliflozin, have been added as potential therapeutic tools in improving the outcome of IgA nephropathy. Only one such report is available. Although the FDA has approved this drug, dapagliflozin for the treatment of chronic kidney disease in the absence of diabetes, we're still a little uncertain as to whether it will become the standard of care in all patients with IgA nephropathy. These mainly renin angiotensin system, whether without added sodium-glucose cotransporter-2 inhibitors represent standard of care. Glucocorticoids in varying dose duration and formulation have been thought to add significantly to an improvement of outcome, but this remains controversial. It may be settled in another few weeks when a very large, the largest trial ever done with glucocorticoids is reported at the American Society of Nephrology Meetings on November 6, 2021. So this slide may change after that date. Next slide. There is very strong and compelling evidence exists that the activation of the complement pathway out of the lectin or alternative pathway or both contribute to the kidney injury and the progression of IgA nephropathy. Next slide. All I've done here is to take the complement cascade and superimpose all of the studies that have been reported in the literature to have an effect on IgA nephropathy to dampen inflammation and improve histology and these are -- involve the complement pathway at various sites, predominantly the C3 step, but also downstream and also the lectin pathway. Next slide. There are a number of investigational agents that are currently being studied for treatment of IgA nephropathy, including B-cell therapy, mesenchymal stem cells, endothelin antagonists and Nrf2 agonist bardoxolone, but my focus here is on complement inhibition. And virtually every protein that is involved in the complement cascade is being studied. And of course, today, we're focusing largely on the C3 step in the complement cascade, which has been nicely reviewed by Hamid. Next slide. Let's move for a few minutes to C3 glomerulopathy. Next slide. Unlike IgA nephropathy, this is an uncommon disorder, less than one patient per million population per year is diagnosed. But like IgA nephropathy, it can only be diagnosed by kidney biopsy, which includes both immunofluorescence and electron microscopy. The pathogenesis of C3 glomerulopathy, unlike IgA nephropathy is likely very heterogeneous, but activation of the alternative pathway is a key step in most cases. Next slide. These patients can present in a fashion similar to that of IgA nephropathy with asymptomatic hematuria but they are more likely to develop marked proteinuria, massive proteinuria and what's called the nephrotic syndrome, which leads to swelling of the ankles and a low serum albumin concentration. And some of the patients like IgA nephropathy can develop a very rapidly progressive form of disease and wind up on dialysis or being candidates for kidney transplants within a few months of the onset of disease. Fortunately, that's fairly uncommon. Next slide. The pathology of C3 glomerulopathy is fairly heterogeneous. The dominant pattern light microscopy of kidney biopsy is what's called a mesangial proliferative or membranoproliferative pattern but crescentic glomerulonephritis can be seen. The immunofluorescence pattern is key to the diagnosis. Because in C3 glomerulopathy, there is either exclusively or dominant C3 deposition usually without other complement components being deposited such as C4 or C1q. And the electron microscopy shows 2 different patterns, subendothelial electron-dense deposits, which is most common, about 85% and about 15% have intramembranous electron dense deposits. Next slide. Here are the 2 electron microscopic patterns seen in C3 glomerulopathy, the C3 glomerular nephritic form C3 GN shows subendothelial electron deposits. This is a glomerular capillary. This is the urinary space. This is the blood space. This is the base of membrane and these electron-dense deposits are accumulated in a subendothelial location. This is the alternative and less common form of C3 glomerulopathy in which the electron-dense deposits are within the base of membrane itself, very dense, [ sausage like ], and these contain complement components, particularly the third component of complement in the deposits themselves. Next slide. Now the pathogenesis of C3 glomerulopathy is not like the 4-step pathogenesis of IgA, there are genetic forms of C3 glomerulonephritis in which mutations of various proteins, such as complement Factor H or complement Factor H related proteins are responsible. Older patients may have a neoplastic disease with monoclonal proteins, gamma globulin proteins which inhibit the action of the regulatory function of complement Factor H on C3b and cause persistent activation of C3. Many patients will have autoantibodies to complement Factor H. Some patients may have underlying infectious diseases and there'd be other mechanisms that we're not completely certain about. Next slide. The treatment of C3 glomerulopathy is highly uncertain. There is a huge unmet need for treatment because there are no randomized controlled trial. Steroids with or without mycophenolate mofetil might be effective in some cases, and in fact, such treatment is suggested in the 2021 version of the KDIGO guidelines. But there are no randomized trials, and we really would be very, very helpful to have a new novel therapy, particularly one that would affect the underlying pathogenesis of C3 activation. Eculizumab, the C5 monoclonal antibody, the anti-CD5 monoclonal antibody might be effective in some cases, but it's mostly limited to those uncommon severe cases or recurrent disease in the transplant. Next slide. There are a number of investigational agents involved in C3 glomerulopathy, including, as we'll discuss today, C3 and other complement inhibitions, monoclonal antibody to CD20, chemotherapy and liver transplantation. Of course, this would only be useful for patients with a genetic mutation in complement Factor H. Next slide. So in summary, both IgA nephropathy and C3 glomerulopathy are very attractive target diseases for complement inhibition therapy. Multiple targets within the complement cascade are viable candidates for testing of efficacy and safety, and of course, complement -- the main target of the complement cascade is the alternative pathway, which involves as a central protein C3 itself. I hope this will be helpful in preparing yourself for questions. And thank you very much for the opportunity to discuss this briefly. Thanks.

Thanks very much. Next slide, please. So now I'll introduce Dr. Peter Browett, who is a world-recognized expert on the hematology side, specifically with -- on PNH. So we're very fortunate to have Dr. Browett talk today. Peter, do you want to take over?

Thank you, Vince. Go to the next slide, please. So my name is Peter Browett. I'm a hematologist at the University of Auckland in Auckland, New Zealand. And I have an interest in a number of areas of hematology, including PNH, and we've been involved in a number of clinical trials. And one of the reasons for that is that New Zealand is one of the few developed countries where there was no funded therapy for PNH and eculizumab is not funded. So our patients are not on complement inhibitory therapy. So what I wanted to do is just give a brief overview of PNH, what the clinical problems are with it, what our current treatment options are, what the issues are with that and where the opportunities might lie. Next slide, please. So PNH is -- it's a rare disorder. It's, I guess, in the literature is considered as an ultra-orphan condition because the incidence is around 0.5 cases per million population. But with modern therapies, improved care, the prevalence has increased and it will only continue to increase. So the prevalence is around 16 per -- for million population. It's due to a mutation, a symmetrical acquired mutation in the hematopoietic stem cell that results in loss of key complement regulatory proteins, CD55 and CD59. And so that results in dysregulated complement activation. So Hamid has very nicely outlined complements critical part of our immune system and loss of these protein results in overactivation of the complement pathways. The traditional name is PNH, paroxysmal nocturnal hemoglobinuria, but it's none of those. It's neither paroxysmal, it can occur chronically. It occurs not just at night and not all patients have hemoglobinuria, which we have the breakdown of hemoglobin components in the urine. So really, this is really a multisystem complement disorder. Next. So as I said, this is due to a mutation within the PIGA gene. And so that results, if you look at the top panel, you can see between the key complement regulatory proteins, CD55 and CD59, they're anchored into the cell membrane and loss of those proteins, as you can see in the middle part of the diagram, is that you have loss of expression of those regulatory proteins. And the consequences of that is that allows dysregulated complement activation and that has an impact on the red blood cells. Next slide. So the loss of the protein predisposes to intravascular hemolysis. Hemolysis is premature breakdown of red blood cells. And hemolysis can either be intravascular where it occurs within the blood vessels and that's significantly more damaging in a number of ways or extravascular, and I'll come back to that shortly. So as Hamid has outlined is that you can see the complement pathway here, activated predominantly in PNH, we think it's through the alternative pathway but the other pathways are critical. And you can see the key roles of C3 in the terminal part of the complement pathway of C5. And the components of CD55 expressed on the red cells, if you look at this, at the left-hand side of the panel, more proximal part, is inhibitory to the complement activation there, particularly C3. And on the right hand, the more terminal part of the pathway, CD59 inhibits the C5 activation to C5a and C5b and formation. If you remember, Hamid mentioned, the membrane attack complex. So that's the complex, the punches holes or pores into cell bacteria, and in this case, the red blood cells. So it's protective in that against the effects of complement activation on the red blood cells. But when that protein is absent, as we see in the next slide, the next slide, sorry, it's over there. So when that protein is absent, then that allows this dysregulated activation of the complement pathway formation. If we look at the right hand-end of the terminal part of the complement pathway, formation of C5b and then subsequently C6, C7, C8 formation of that membrane attack complex that punches these pores or holes into the red blood cells and results in intravascular hemolysis. And so that causes patients to be anemic. So low hemoglobin and consequent of that. But also as we see in the next slide, is that it's not just the hemolysis and anemia. This is a multisystem disease. Because remember, the original mutation occurs in the hematopoietic stem cell. So these proteins are also absent on platelets and leukocytes. So we have both hemolysis and platelets and leukocyte activation. So these patients have profound anemia. They have a more profound fatigue than for the level of hemoglobin, and that's because of the consequences of the hemolysis and release from a lot of the byproducts of hemolysis but also a lot of other end organ damage and toxicity. So there's an increased risk of thrombosis, particularly intraabdominal venous thrombosis, end organ damage, chronic kidney disease and pulmonary hypertension. And patients frequently have symptoms of abdominal pain, dysphagia, erectile dysfunction. And that's a smooth muscle dysfunction release by abnormal levels of nitrous oxide from the hemolysis. So it's not just an anemia, it's a multisystem disorder caused by complement dysregulation. Next slide. So patients present to a number of clinical services with a number of symptoms, but just the key things to point out would be anemia, as seen at the bottom of this table, thrombosis and multisystem disease. So this is a significant disease that in the absence of treatment is a life-shortening condition. Next slide. So the standard of care treatment outside of New Zealand is with inhibition of the terminal part of the complement pathway. And this is with the C5 inhibitor, the monoclonal antibody. So this is a humanized monoclonal antibody eculizumab, which is given by intravenous infusion that Hamid mentioned lasting 2 to 3 hours every 14 days. The next slide, please. So the inhibition with eculizumab, it inhibits that terminal component, as shown in the box, of the C5 activation formation of the membrane attack complex and that inhibits the consequences of their complement dysregulation. So hemolysis, the increased inflammation and the consequences of that and thrombosis. Note that it had no impact on the more proximal component of a complement pathway, particularly that key component around C3 and C3 activation. Next slide. So this was really a significant breakthrough and treatment of PNH. And studies clearly show it improves overall survival and quality of life for patients with eculizumab. We look at the initial key studies that result in the FDA approval is on the left-hand panel is the outcome for patients with PNH compared to age and sex match controlled pre-eculizumab. So the green survival curve is for the PNH patients. And on the right is the post eculizumab compared with age and sex match controls. So you can see significant improvement in quality of life and survival. And this has been shown in follow-up studies, including registry and real-world sort of studies. Next slide. So you may then ask well, given that, what are the issues? Where is the unmet need? What are the issues for me as a clinical hematologist and for our patients? And there are a number. And these are summarized. Some of them are here on the slide. So not all patients had optimal control of the hemolysis. Secondly, there's the -- because we're not only inhibiting the terminal part of the pathway, there's the risk of extravascular hemolysis because of the accumulation of C3 on the red blood cells. As I've mentioned and as Hamid mentioned, this is a treatment that involves lifelong antibody replacement therapy, so 2 weekly infusions of the antibody. And finally, there's the risk of an infection from encapsulated bacteria so children that are born with mutations within their complement pathway have a higher risk of bacterial infections, particularly meningococcal infections. And so these are ongoing issues despite the improvement in outcomes with eculizumab. Next slide. So if we look at intravascular hemolysis, so this can be both pharmacokinetic and pharmacodynamic. So some patients estimated to be 10% to 15% of patients will have breakthrough hemolysis towards the coming up today 12, 13, 14 after their last infusion of eculizumab. So that's due to suboptimal levels of antibody and suboptimal inhibition of the C5 sort of complex. And so our approach there would be to either increase the dose of eculizumab or to reduce the timing of the frequency of infusions. Pharmacodynamic breakthrough is really where there is overwhelming activation of the complement pathway, for example, with infection resulting in breakthrough hemolysis. And finally, there are a rare group of patients that have mutations within the C5 and that alters the binding of eculizumab. So that breakthrough intravascular hemolysis and the main issue being the pharmacokinetic in suboptimal levels prior to the next infusion. The next slide. Probably -- not probably, definitely a bigger issue is the emergence of extravascular hemolysis. Next slide. So with eculizumab, as you can see on the right-hand end of the panel, where we inhibit C5 as we're inhibiting that terminal part of a complement pathway but that still allows for activation of C3. And if you look in the middle of this complement pathway, it is that there is accumulation of C3 because we've got lots of CD55 expression. C3 accumulates on red blood cells. And as Hamid mentioned, C3 is an opsonization tag. And so red cells with C3 on can then be opsonized and taken up not within the red blood -- not within the blood system, but by macrophages that recognize C3 within the liver and spleen. We call this extravascular hemolysis. And this can occur in 20% to 25% of patients, although they've got control of their PNH and inhibition of C5, as they've got extravascular hemolysis due to C3 accumulation. And this is a significant issue with terminal complement inhibition. Next slide. As we've mentioned, there's the requirement for lifelong intravenous infusions and we can't underestimate this. I saw a patient in my clinic on Friday who -- he's a young student. Was devastated with PNH. Had an appalling quality of life with regular transfusions. And we [went heavy] eculizumab, and she's now gone on to a clinical trial with actually an oral-based therapy, and it's just turned around her life. She's now a student in another city and doing the things that 19- and 20-year-old students should do and that we don't really need to know about. So I think -- I can't underestimate how important that is. And next slide. So there have been some advances, and Hamid showed this sort of slide, is that there is now a longer-acting C5 inhibitor: ravulizumab. So this is given 8-weekly. But it's still -- it is still an infusion every 2 months. So patients need to present to an infusional center, for this. There is still the issue of C3 accumulation and extravascular hemolysis. So it's an advance, but it still doesn't overcome all the issues. And the final area of unmet need with complement inhibition in my next slide is the risk of meningococcal infection. And the next slide is that all our patients will be immunized against encapsulated bacteria, including meningococcus but there is still a breakthrough of an meningococcal infections shown in this recently published sort of study and many centers would put patients onto long-term antibiotic prophylaxis. Next slide. So with that, what are the options for how do we overcome these areas? So next slide. So with the breakthrough hemolysis, we can look at what are more effective strategies for complement blockade. For the extravascular hemolysis, next slide, is that we need to look at the proximal inhibition of looking at that inhibition of either C3 or even more proximally than that looking at alternate pathway inhibitions. And the next slide is, is there a treatment that's got an easier option and a longer delivery time? Next slide. So this is a complex slide, but what I've got is it's taken from a recent review. And if we look on the right-hand panel in blue are the current C5-based therapeutics. So they're not going to overcome this problem, the biggest problem of the C3-based hemolysis. So the strategies are more proximal inhibition. So that's either targeting the alternate pathway as shown in the top left-hand panel. And so there are activity in that area. And as we're discussing today, looking at C3-based inhibition. And I think that's where the [promise holds] because that's a key component. And to the next slide. And we have proof of principle from that on my next slide. And this slide. This is the PEGASUS trial and Hamid showed this, but I'll just go over it again because I think this is key. So this was a proof of principle study with Pegcetacoplan. So this is a specific C3 inhibitor. And what they took in this study were patients with PNH who are on eculizumab but had an ongoing anemia. So hemoglobin less than 10 grams per deciliter, so they were needing transfusions. And this was because they had C3-mediated extravascular hemolysis. Remember, this is around 20%, 25% of patients. They had a 4-week run-in period, as shown on the left-hand part of this graph, where patients got both the C3 inhibitor and eculizumab together. And you can see the improvement in the hemoglobin. Then patients were randomized to either -- for a 16-week trial period for either the C3 inhibitor or going back on to eculizumab. And so you can see clear difference in the hemoglobin levels and the C3 inhibitor group versus those that went back to eculizumab. So this is proof of principle that C3 inhibition is effective at overcoming that C3-mediated extravascular hemolysis. Next slide. So just, in summary, is that PNH [indiscernible] it's a multisystem disease of complement dysregulation. It's not just hemolysis. That C5 inhibition has been an improvement, but there are many questions left to be addressed, particularly the management of extravascular hemolysis. And we've seen from the PEGASUS trial, this potential benefit for targeting proximal complement pathway of sort of C3 inhibition. So thank you for listening, and I'll be happy to take questions at the end of the presentations.

Thanks very much. That was very helpful. Now James Hamilton will talk about the ARO-C3 preclinical data and describe what our early clinical program's going to look like. James?

Sure Thanks, Vince, and thanks for those great presentations from Dr. Glassock and Dr. Browett. If you go to the next slide, first, before getting into the data, I wanted to describe and reiterate something that Vince mentioned earlier, and that is that the design of ARO-C3 is quite similar to our other liver-targeted siRNA drugs, including compounds like ARO-AAT, ARO-ANG3 and ARO-APOC3. And I say that because those molecules have demonstrated a deep reduction of their gene target expression, respectively, for all 3 of those with long duration of effect and we would expect the same or a similar effect out of ARO-C3. And so here on this slide, this is -- these are data from a monkey study, a dose-range-finding study where we dose escalated in cynos starting at 0.5 mg/kg and dose escalating through 4.5 mg/kg and at the highest dose level we're achieving gene target silencing measured by serum C3 of about 75% to 80% with duration of effect extending out past 8 weeks after the last dose. In this study, the maximum serum C3 reduction was 90% and this was associated with the reduction in hemolytic activity that you see on the right panel along with the long duration of effect that is characteristic of this class of molecules. So we can go to the next slide, and I'll touch briefly on the planned clinical study. We had -- as we announced yesterday, we have filed to initiate a Phase I/II dose escalation study to evaluate the safety, tolerability, PK and pharmacodynamics of ARO-C3. This is a 2-part study. We start in healthy volunteers and [indiscernible] Part 1 of the study is a fairly straightforward, single escalating dose study that's placebo-controlled and then based on the results from Part 1 at both safety and pharmacology results, we will select doses for use in Part 2 of the study, which is the patient component of the study. And that Part 2 of the study will enroll patients with PNH, patients with C3G and patients with IgA nephropathy. And Part 2 of the study is all open labeled. We expect to begin dosing in the first quarter of next year. And if you go to the next slide, there are some details on each of these components of the study. Again, Part 1, healthy volunteers, placebo-controlled, single-dose escalation up through a single dose of 400 milligrams. And then we will follow these patients out for a fair amount of time to get a good feel for duration of activity. If you go to the next slide. Once we have sufficient pharmacology data and safety data from Part 1 of the study, we will select the dose to be used in Part 2 of the study. We'll actually select 2 doses for the PNH part of the study. We enroll high- and low-dose PNH cohorts. So Cohort 5a is the low-dose cohort in PNH patients that are not on treatment and then Cohort 5b is the higher dose, also in PNH patients not on treatment, whereas Cohort 6a and 6b are again, respectively, low dose and high doses in PNH patients that have had a suboptimal response to C5 inhibition. And once those are open, the a and the b cohorts enroll sequentially, but we are able to, in parallel, open the renal disease patient cohorts. So Cohort 7 is in C3 glomerulopathy and Cohort 8 in IgA nephropathy. Again, all open label. Next slide. And so Vince, I'll hand it back over to you for a wrap-up.

Thanks, James. Go ahead and switch to the next slide, please. Okay. So we've heard a lot of detail today. And so I just wanted to kind of summarize what are the key points here. So what do we know about the field, generally? I think it's clear. Complement C5 inhibitors have moved the needle, have changed the lives of many patients. They are disease-modifying agents that are FDA approved. Also, what I think is very clear is that there still remains a substantial amount of unmet need, both on the nephrology side as well as the hematology side. And then lastly, and I think one of the really important takeaways from today, is there is clinical validation for the more proximal C3 step of the complement pathway. And that's important. Next slide, please. So what makes us confident that ARO-C3 may play a role in future treatment. As I mentioned, proximal C3 inhibition, and several folks mentioned this today, may confer advantages over inhibiting at the C5 step. Next, there are multiple commercially attractive opportunities with a C5 inhibitor. So this is an overused term, but this could be a pipeline in a product. There are several areas where we can really make a difference for patients and several diseases that might be addressed here. Next, an RNAi-based C3 inhibitor has substantial dosing advantages over other investigational therapies and other MOAs. Next, ARO-C3 is the first clinical stage RNAi-based candidate, which is something that we always strive to do. We want to develop the most optimal investigational products, but we also want to be fast. And I think we met that here. And James hit on this, and I mentioned it at the outset, but this is a really important point that where we see a big benefit to Arrowhead's platform is that everything that we learn from prior programs gets built into future programs. So this ARO-C3 candidate is built on the -- basically the shoulders of several other products that we have developed that are targeting liver expressed proteins. And we think that this -- that our TRiMTM system targeting liver expressed proteins is validated. I think we have proven that we're very good at getting deep and durable knockdown of target genes. And the duration of effect is a critical differentiator here from other mechanisms of action and also that our safety and tolerability profile has been very consistent, and we hope that folks see that here with ARO-C3 as well. And last, and this should not be left off. This is a really important point. I think Arrowhead has a really good track record at executing in the clinic, and this program is no different. We have a design that we think has the potential to get us rapid clinical proof of concept, not only for pharmacology in healthy volunteers, but directly in the patients that we hope to serve in the future. So it's -- this is a really exciting program for us. It's moved very rapidly. And now I'd like to open up the call to questions from the analysts. And I want to thank all the panelists today. Thank everybody at home for listening to us. So Sarah, do you want to go ahead and activate the first question?

Yes. Thank you, Vince. [Operator Instructions] And our first question will come from Mayank Mamtani at B. Riley.

Can you hear me okay, Sarah?

Yes.

Excellent. I appreciate the level of detail here. So maybe first question for Dr. Glassock. I was just curious with a targeted modality like this and where we are with the complement cascade pathway. What would be helpful if you could talk to the levels of proteinuria reduction that you'd anticipate? And then maybe also put in context the data we saw earlier in the year with Factor B inhibitor, for example. So that's on the efficacy side. And also maybe talk to the risk of infections. If you're chronically knocking down C3 to the extent we are talking about here, Dr. Glassock.

Well, if I understand your question correctly, it's twofold. What kind of extent of reduction in complement activation is going to be required to show a beneficial response and what are the risks of infection in patients treated with complement inhibition agents. I hope I've got the answer -- I hope I've got the questions correctly.

That's perfect.

Well, of course, we're in a very early phase of development of complement inhibition with a relatively small number of long-term studies, which are adequately controlled. It does not appear at this moment that it will require a 100% reduction in the level of these complement proteins in order to achieve a beneficial response. But we don't know whether a 25%, a 50% or a 75% reduction is going to show a graded beneficial response in terms of, say, a surrogate outcome measure like proteinuria or change in GFR for kidney disease. That will require, I think, more information. We do know that any complement inhibition would likely enhance the probability of an infection with an encapsulated organism. Meningococcus, certain forms of Streptococcus, but that it may not produce a generalized enhancement of infection risk to say viruses, protozoa, other organisms. Whether the programs that are in place for immunization and long-term prophylactic antimicrobials will be required in all instances is a question that will subsequently need to be answered. I suspect that some sort of chemoprophylaxis for potential infections will be a part of the regimen of therapy for many of these complement inhibition strategies, including C3, but it could be that the level of complement inhibition required for a beneficial effect is not going to be associated with a great increase in infection risk. That would be a best case scenario. And I think the studies that are designed and currently in progress will give us some kind of an answer to that very appropriate question. I hope my answer -- it's not complete because the data isn't there to make a good, solid answer.

And just, may I follow up on how to get to that data. So maybe for James or Javier. How should we think about you going through this SAD/MAD? I think historically from other programs you go through them quickly. Can you talk like what sort of a mandate for data releases you may have? And then I think the top question in everyone's mind is, what sort of target product profile you're kind of aspiring for as you also get into the patients?

Go ahead.

I can comment on the question on the data release. I mean the -- so the patient cohorts are all open label, and so we will have a good look at the data as we go along and we follow the patients out for a long period of time, including the IgA nephropathy patients, so even if it takes 6 months of complement inhibition to see changes in urine protein levels or some of the other biomarkers, we should be able to see that later in the study. But I think since the study's open label, we'll have a good opportunity to release data along the way at relevant medical conferences. Did that get at part of your question?

Yes. SAD/MAD, before you get into patients, would you release that -- the kinetics of the doses that -- how you're knocking down C3?

Yes, I think that is fair game as well. And it's -- just to be clear, for the healthy volunteer part of the study, it's only a single escalating dose at this point. We don't have any MAD component in the study right now.

Yes. The single ascending dose portion is in healthies. The multiple dose portion is directly in patients.

The next question comes from Joel Beatty at Baird.

Thanks this great presentation today. The first question is, do you anticipate that the method of lowering C3 antibody could matter for efficacy in these patients for example, with -- impacting the production of C3 with this agent versus binding to it with other agents.

James, do you want to...

I can take a shot at that and then if there's any thought from the panel members. I mean I think given that the real perpetrators of the injury are downstream of C3 and related to cleavage of C3, I mean, I would think if you're able to take out C3 itself that, that should have the same or similar effect as binding to and inhibiting at C3 and C3b just through the protein binding mechanism of action. I guess the data will tell us one way or the other, but I don't see a definitive difference of inhibiting C3 and all the downstream occurrences one way versus the other.

I can make a comment here that may be potentially helpful. When C3 is formed at the interface of tissues, it covalently links with underlying tissue molecules. So C3 deposition is an important component of the pathological consequences of complement activation. It's not simply the fact that there are soluble pro-inflammatory molecules spun off of the molecule like C3a or C5a but there is an important element of the actual deposition of C3 protein in tissues. This has been best shown in the course the red cell in PNH, which becomes bound to the erythrocyte membrane, but there are similar deposition of C3b in the kidney of patients with -- particularly with C3 glomerulonephritis which can interfere with glomerular function and participate in the generation of proteinuria, entirely independent of the soluble pro-inflammatory molecules that are generated in complement activation. When you treat a patient with C3 glomerulopathy with eculizumab, the amount of deposits of C3 do not change, although the patient may exhibit some transient improvement in hematuria and proteinuria. So the element of being able to treat proximal C3 activation, I think, is a major component of the potential benefits of this Arrowhead project.

The next question comes from Luca Issi from RBC.

Can you hear me okay.

Yes. We can hear you.

Terrific. I have 2 quick questions. The first is on differentiations versus [hepalus]. And maybe the second one on dosing. So differentiations versus [hepalus], obviously, you talked about a dosing advantage, which is substantial. However, how should we think about the targeted tissue. Obviously, the siRNA will primarily knock down C3 and deliver versus maybe the [hepalus] molecule may have a broader impact to tissues as well. So again, wondering if you can comment on that and whether that could be a potential limitation of a siRNA here? And then the second one on dosing. The slides went pretty fast, but if I saw it correctly, you're going up to 400 milligrams. If I recall it correctly, for A1AT, you went up to 200 milligrams and for APOC3, we're at 100 milligrams. So wondering if you can elaborate on why do you have to go to relatively high doses versus other [programs] than we've seen in the past?

Sure. I think on the first part of the question about inhibition of C3 locally, I mean, we specifically target hepatic expression, which is the main source of circulating C3. It's true we would not hit any local production of C3 in inflamed tissue. But I think -- and again, some of the panelists might have thoughts on this, the bulk of the expression of circulating C3 will be that coming from the liver. And then the question of dosing, we have quite a range at which we could dose and we have done so in other programs. I think in our -- for example, in our HBV program, we went up to 400 milligrams in -- at ARO-ANG3, we went up to 300 milligrams and AAT, as you mentioned, we went up to 200. I think we'll see. I mean, we wanted to include a wide range of doses to catch the top of the dose response curve and 400 may be too high. We may hit that at 100 or 200. So the intent here is to provide a range to understand dose response. And I think going from 50 to 400 likely captures that range somewhere in between. I don't think -- there's nothing inherent about this molecule that we have to dose higher. We're just trying to understand dose response.

[Operator Instructions] With that, the next question will come from Alethia Young at Cantor Fitzgerald.

Just, I guess, a simple question is, obviously, Empaveli's on the market, obviously, Alexion has their own franchise products in the market. What do you think about clinical development? I mean, do you think you're going to need to like run some sort of head-to-head or...? Or how do you think about kind of the clinical development strategy if you were to move forward after the kind of Phase 1 work?

Yes, I can touch on that. I mean even in the current study, we are investigating this molecule in combination with patients that are on C5 inhibitors that have had a limited response or maybe not an ideal response and then going forward. I mean, it's certainly a possibility to investigate combinations or head-to-head versus a C3 inhibition versus C5 inhibition down the road and later-stage clinical studies.

And that -- specifically for PNH, you're talking about.

Correct.

There's certainly opportunities where there's no standard of care, and there will not be a comparator for -- or there likely will not be a comparator for the clinical studies.

Right. I was speaking for PNH.

The next question comes from Patrick Trucchio at H.C. Wainright.

Just 1 for Arrowhead. Can you discuss the potential impact, if any, at this stage from the COVID pandemic on initiating the Phase I program and on the potential pace of enrollment?

Yes, sure. I can address that question. It really has not impacted study start-up in New Zealand. I mean new Zealand has been not totally unscathed. And I guess, I defer to Peter as far as how are things going COVID-wise in New Zealand. But our time lines for this program relative to some of our fastest programs from the point of when we had an idea and decided that we were going to pursue a certain target all the way through the CTA filing. This was one of our fastest and -- that matched the speed of programs like ARO-HBV or ARO-AAT. So COVID really had not impacted study start-up and launching the studies at -- my understanding is that things are going reasonably well in Auckland and not preventing healthy volunteers from coming to our trial site. So for the healthy volunteer component of the study, I don't see a huge impact from COVID. The patient part of the study is a little bit further off in the future. Maybe -- it's tougher to predict if or how that would be impacted. But I don't see any near-term impact of COVID directly on healthy volunteer enrollment.

[indiscernible]

Sure, Peter.

And so New Zealand pursued an elimination policy. So we had no COVID in the community. So [indiscernible] where those trials are being initiated, have had normal practice. We've now got Delta variants. So there is low levels in the community, and we're moving to the nation sort of a -- high levels of vaccination and more of the sort of suppression [indiscernible] the rest of the world. But we've moved -- the trial activity is -- the level we're at, at the moment is -- the healthy volunteers can come in and out for their treatment. So where things were slow for about 3 or 4 weeks, but they're getting back to normal again.

The next question will come from Esther Rajavelu at UBS.

You can hear me well?

Yes.

Perfect. So I guess I thought I saw a slide there with the NHP data with about 90% knockdown. And I'm curious to see if you have any thoughts on [indiscernible] for that level of knockdown in humans.

So is the question, is that level of knockdown achievable in humans based on what we've seen in the cyno?

Exactly.

Yes. I mean, historically, our performance in the cynos has translated very well into humans. And if anything, we tend to gain depth as well as duration of knockdown in going from cynos to humans. And you can see that if you look back at some of our old ARO-AAT cyno data that the duration and the depth at a given dose was better in the humans versus the monkey. So I certainly think it's achievable in the humans based on what we've seen in the monkeys.

Got it. And if I can squeeze 1 more in. Does the C3 convertase have secondary substrates that may act on in the presence of inhibitors, C3 inhibitors?

Yes, I just have to give that one to Hamid or maybe Peter.

Not that I'm aware of, I haven't come across other substrates for C3 converters in my readings. I don't know, Peter and Dr. Glassock, have you come across any literature about other substrates?

Not that I'm aware of either.

Yes. That's a very good question. I don't have a good answer for it. I would have to go and look and see what the precise active site is for the C3 convertases that are developed as a consequence of classical and alternative pathway. There are 2 different convertases, of course: the one that is developed through the classical pathway and the lectin pathway and the other through the alternative pathway. Both contain C3b. Therefore, both would be affected by an inhibition of C3 synthesis, but I can't answer that question directly. It's a very good question.

The next question comes from Mani Foroohar from Leerink.

This is a compound question. This is a result of listening to Alethia's question as well as Mayank's. Putting aside any commercial concerns, is there a rationale for enrolling the clinical trial, in at least some of these indications in geographies where SOLIRIS and ULTOMIRIS are either less full reimbursed, less broadly adopted and used? And then secondarily, as you think about starting dose and dose escalation, is there any difference in terms of how you think about what the proper starting dose and ultimate potential max dose would be between indications? And does that also influence how you might think about where you run a study and at what doses you start running each indication?

Yes. Sure. I mean I think the first question is dead on. I mean, I think we would certainly want to go to -- at geographies for part of this study or future studies where C5 inhibitors are not available, so we can study the molecule in a naive population. And then the second question on doses. I mean, I think we'll have to see. We have, in the past, tweaked the study and added cohorts, healthy volunteer cohorts to better understand that dose range finding certainly also doable in the patient cohorts if we felt like we needed to alter the doses to get better knockdown. I wouldn't expect that the RNAi mechanism of action is different in the healthies versus the patients in knocking down C3 in the hepatocyte, C3 expression. It should be the same -- so -- but the data -- we'll have to see what the data show from the study, but that's what I'd anticipate.

Great. That's very helpful.

The last question we'll take will come from Ted Tenthoff at Piper Sandler.

Actually, most of my questions have been answered. But I was wondering if maybe there would be the opportunity, since this is a different mechanism to be used in combination with other agents, including the C5-targeting antibodies, especially in patients who maybe aren't meeting threshold or aren't being sufficiently -- resolving their symptoms.

Vince, do you want to take that one?

Sure. Well, I think that's actually part of the design of our first [demand] that we will have cohorts looking at those not well controlled on C5 as well as those naive. So if you're asking for -- commercially if we see this as add-on therapy, we're just going to have to see where -- where these data lead us. But to the point of multiple ones of the presentations today, we still see for patients who are well controlled, substantial opportunity and unmet need in those who need a little bit more help and those that may be better suited with a more proximal part of the complement pathway. So we see opportunities on both side of it. We haven't made a decision on which way this will go. And certainly, the data will lead us [indiscernible].

This concludes today's verbal Q&A session. I would now like to turn it back to Vince for any concluding remarks.

Well, thanks so much, and a huge thank you to Dr. Glassock and Dr. Browett. We really appreciate your insight here. It's enormously helpful to us, and I know it's enormously helpful to the investment community. And thanks to everybody at home for taking the time, and we'll talk to you soon.