Good afternoon, and welcome to the Arrowhead Summer Series of R&D Webinars, Part 3. As a reminder, all participants are in a listen-only mode. The event is being recorded, and a replay and a PDF version of the slides will be available on the Arrowhead website following the conclusion of the call. I would now like to turn the call over to your host, Vincent Anzalone, VP and Head of Investor Relations. Please go ahead. Thanks so much, Sarah, and thanks, everybody, for joining us today. Before we start, I just wanna let everyone know we will be making forward-looking statements today, so please refer to our SEC filings for risk factors. This is Part 3 of our 2024 Summer Series of R&D webinars, and we'll specifically be covering our pulmonary pipeline, which includes our clinical pipeline, which includes ARO-RAGE, ARO-MUC5AC, and ARO-MMP7. Just to reiterate, the purpose of the 2024 Summer Series is to give folks some insight into some of the underappreciated parts of our pipeline that we don't get to talk about too, in too much detail. Second, to cover some of the advances that we're making to the TRIM platform that allows us to get to multiple different tissue types. Third, to hear directly from the Arrowhead team that works on these programs. And then lastly, to get some external physician perspective on the disease areas and the targets that we're, that we're working on. I think today, that's especially important, because it's very clear, that the targets and the pathways, for the pulmonary platform are very complex, particularly the RAGE pathway. And so, you know, we're very lucky to get some insight into how that RAGE pathway operates. So here's the basic agenda today. I will cover some... an overview. James Hamilton, our Chief of Discovery and Translational Medicine, will go over the pulmonary platform broadly. Dr. Matthias Salathe will cover the RAGE pathway. As I mentioned, it is very complex, and he'll try to simplify it as much as possible. John Huetsch, who's Head of Clinical Development for Pulmonary, Dr. John Huetsch, I'll say, will give an update on our clinical studies and the design. I'll come back with some concluding remarks, and then we'll have some time for Q&A at the end. So I just wanna quickly introduce Dr. Salathe. He has been one of our advisors and has participated in some of our other presentations, investor-focused presentations for the last few years. He is a professor and Chair of the Department of Internal Medicine and Vice Chancellor of Research and the Interim Executive Vice Chancellor at the University of Kansas Medical Center. He is an expert in the biology of that RAGE pathway. We're very, very fortunate to have him here today. So please, all the analysts, you... Don't hold back on questions. He will have the answer for all of this complex biology of the RAGE pathway. So Arrowhead, generally, who are we? We are an RNAi therapeutics company with a broad pipeline of wholly owned and partnered products. We have 14 clinical-stage assets today. 10 of those are wholly owned, four are with partners. We think we have a good, healthy mix of early clinical as well as late-stage clinical candidates, and then ultimately a pre-commercial program in plozasiran, which, you know, if you missed it, we did give a top line on our phase III study for the plozasiran program in FCS last month. And we are pleased to announce that we will be presenting full phase III data for plozasiran at the European Society of Cardiology meeting in early September. So please stay tuned for more details on that. The platform that we use, the technology platform that we use is called Targeted RNAi Molecules, or TRIM. And James will talk a bit about how we've adapted this TRIM platform specifically for lung delivery today. And then lastly, we think we have the financial resources to exploit value or to create value and exploit all of the assets in the future. And we also have access to additional non-dilutive sources of capital to continue to fund operations until we have commercial revenue in the not-too-distant future, that will become an important source of financing for us. So this is what our pipeline looks like. It's very broad, and as I mentioned, the purpose of these summer series of R&D webinars is to go in detail about specific therapeutic areas. You know, as you can see, we have cardiometabolic, pulmonary, liver, neuromuscular, and then other programs. These are all clinical stage assets. And so today, we're gonna focus on these three programs: ARO-RAGE, ARO-MUC5AC, and ARO-MMP7. These are our first three programs that use our pulmonary-targeted TRIM platform, and these are all in clinical studies right now. So now I'll turn it over to Dr. James Hamilton, who will go over our pulmonary platform in more detail. Thank you. James? Sure. Thanks, Vince. So first, just a refresher on the platform and the chemistry. It's very similar to what we use with the liver-targeting platform or so-called GalNAc, with a few key differences. The pulmonary platform uses the same algorithmic process that we use for GalNAc sequence selection, so the same process for selecting the siRNA sequences. We do, however, use different modification chemistries to improve the siRNA potency with the pulmonary platform. We do use a different targeting ligand, specifically a small molecule targeting the alpha-v beta-6 integrin receptor, and this is used to drive the siRNA into the alveolar epithelial cells. We've learned a lot about this delivery platform based on, not only clinical, but also a lot of non-clinical experience, and we've learned that the platform is most efficient at delivering siRNA into the deep lung, and this coincides nicely with where targets like RAGE are expressed. However, where the platform delivers most efficiently to is not only, not always a good match with where biomarkers can be measured. For example, things like brush biopsy or airway swabs largely sample the proximal airway. BAL, for example, measures samples, the proximal as well as the distal airway, so we're able to usually get a good assessment of what's going on in the deep lung with, the BALF samples. And then, luckily for the ARO-RAGE program, we have a serum biomarker measuring soluble RAGE, which again, primarily comes from the epithelial cells in the deep lung. A refresher on the specifics of RAGE as a target. RAGE or mRAGE, specifically, the membrane-bound RAGE, is a pro-inflammatory pattern recognition receptor. The ligand binding drives lung inflammation through both Type 2 and non-Type 2 inflammatory pathways, and in rodents, RAGE knockout or knockdown protects the animals from Type 2 and non-Type 2 inflammation. So the RAGE pathway is, is pleiotropic, and the inflammatory pathways that it works through, involve multiple different, both Type 2 and non-Type 2 cytokines. Type 2 cytokines, including things like IL-33, TSLP, IL-4, IL-5, IL-13. Yet RAGE is also involved in activation of the NLRP3 inflammasome pathways by inducing cytokines like IL-6, IL-17, MIP-1 alpha, and others that are responsible for neutrophilic inflammation. With the broad anti-inflammatory effects anticipated with RAGE silencing, we've continued to study how RAGE inhibition impacts animal models of various inflammatory airway diseases, and we've presented data several times previously, demonstrating the ability of RAGE inhibition to blunt the Type 2 inflammatory response in a rat model of allergic asthma. However, new and ongoing work have revolved around models of neutrophilic inflammation, represented by the acute lung injury model, as well as animal models of emphysema. Here we show that RAGE silencing can attenuate various neutrophilic inflammatory mediators, and in this study, the animals were first treated with a rat cross-reactive siRNA or placebo to silence RAGE. This was followed by an intratracheal dose of LPS or lipopolysaccharide to induce neutrophilic inflammation. In this rat LPS model, RAGE silencing prevents induction of neutrophilic inflammatory pathways as measured by key inflammasome mediators, again, such as IL-1 alpha, IL-1 beta, TNF-alpha, and IL-6, as well as others, and you can see the reductions plotted on the left. In the same model, RAGE silencing reduces markers of neutrophilic infiltration and neutrophil activity, including neutrophil elastase, shown here on the left, and markers of neutrophil extracellular trap formation, shown on the right. We also think that RAGE inhibition could have a therapeutic role in COPD and emphysema. RAGE expression is increased in the COPD lungs, and exogenous RAGE overexpression causes inflammation and emphysema in mice. RAGE knockout protects mice against elastase-induced lung inflammation and emphysema, and lung RAGE silencing with siRNA or small molecule RAGE antagonist protects the mice lungs against cigarette smoke-induced inflammation and emphysema. So we set out to evaluate the anti-inflammatory effect of RAGE silencing in a rat model of elastase-induced inflammation and emphysema. And here we're showing that in the setting of pancreatic porcine elastase administration, which damages the lung parenchyma and induces emphysema, the RAGE silencing reduces influx of inflammatory cells, including macrophages and neutrophils, which are shown here, while also reducing the proteases responsible for lung parenchymal damage, including things like MMP-2, MMP-9, and MMP-12, which are all markers of emphysema pathogenesis. In the same model, the same porcine elastase-induced model of emphysema, we also see reduction in cytokines involved in neutrophilic inflammation, including, again, IL-1 beta, IL-18, TNF-alpha, and many others depicted here. So we think ARO-RAGE has broad potential as a pulmonary anti-inflammatory therapeutic. We see the potential not only in Type 2 inflammation, including Type 2 high asthma and Type 2 high COPD, but also in neutrophilic inflammation, including Type 2 low asthma, COPD, and emphysema, as well as potentially cystic fibrosis. So moving on to the ARO-MMP7 program. This molecule targets deep lung expression of MMP-7, which is overexpressed in the idiopathic pulmonary fibrosis lung and is a prognostic marker in IPF. MMP-7 is secreted by the aberrant basaloid epithelial cells, and this is a cell type that is unique to the IPF lung. The secreted MMP-7 induces neutrophil recruitment, fibroblast proliferation, and collagen production to set up a pro-inflammatory or pro-fibrotic environment that occurs in the IPF lung. We think inhaled ARO-MMP7 could be used in combination with current standard of care, and the local inhaled route of delivery should avoid systemic toxicities like those seen with some of the other therapeutic modalities available, and that includes the approved drugs that are used to treat IPF currently. Again, the platform delivers best to the deep lung, including the bronchoalveolar junction, and this is precisely where the aberrant basaloid cells reside and overexpress MMP-7. So it's really an ideal target for this platform. And as we've stated previously, MMP-7 expression in the healthy volunteers is actually pretty low and does not localize to the deep lung. So the expression is throughout the lung, since they don't have the aberrant basaloid cells. So we don't expect to see changes in MMP-7 from the healthy volunteer cohorts. However, in the IPF patient cohorts, the increased MMP-7 expression is coming from the deep lung aberrant basaloid cells, and we should be able to measure decreases in MMP-7 in IPF patients using BALF and blood samples. Moving on to the third program, this is ARO-MUC5AC, which targets goblet cell expression of MUC5AC, with the potential to alleviate the mucus obstruction that's part of asthma pathogenesis. In the asthmatic and in the COPD lung, MUC5AC is overexpressed primarily in the bronchioles, leading to small airway mucus obstruction, and our plan is to use sputum MUC5AC levels as a biomarker for target knockdown in the small airways. And, Dr. Huetsch will provide an update on all of these clinical programs later. But now I'd like to turn the floor over to Dr. Salathe, to discuss some of these inflammatory pathways. Dr. Salathe, the floor is yours. Thank you. I actually have to unmute myself, I realize. So what I wanted to do is go briefly through a lot of... actually, a series of slides on RAGE pathways and how they are not only connected to asthma and how we think about that, or how we could think about that in relationship to current therapies like biologics, but also at least briefly, in some other disease, that were, that in the disease that was not mentioned before, COPD in particular. So when we think about asthma first, we have two main sources of inflammation. One is T2 low asthma, and the other one, the other one is T2 high asthma. And most biologics actually, really, and I showed, more data on this, are treating T2 higher asthma. That's true for all of the ones on the market. While they have been used in T2 low asthma, as you're gonna see, there is not as much efficacy of these biologics in this space. So you see here, criteria for remission, and it depends on how you define that. But all the biologics have actually efficacy. But when you look at full clinical remission, they're sort of in the mid-30s, so there is still a lot of room to improve for full remission, at least in the severe asthma types. You see that here, if you look at how you define remission, if you go only in quotation marks with no exacerbation or no long-term oral corticosteroid use, there, all the biologics sort of mixed together have about a 50% success rate. But really, if well-controlled and normal lung function is included, we're going down to about 20%. This is still not ideal in the current therapy world. What's also interesting is that there is actually not a huge difference between the different biologics currently used. You see, specifically in the harshest definition of remission, you get about 20%-25% remission rate with all of these biologics, at least the ones listed here. Now, what's also clear is that tezepelumab has most efficacy in T2 high asthma. If you look here at the plots to the left, tezepelumab, I'm always having trouble with this word. tezepelumab is better if you have a high eosinophil count at baseline, and what's not highlighted here as well is you have a high FeNO value at baseline. That means it is likely T2 high, and that is very efficient for tezepelumab to work. This is here shown if you have eosinophil counts over 300 and a FeNO over 25, you can reduce the asthma exacerbation rate over 52 weeks by about 77%. On the other hand, if you do not have that, the efficacy is much lower, it's about 39%. So again, showing that even in T2 high, there is more room to go, but in T2 low, these biologics, even the best one, here tezepelumab, is not sufficient really to make that big an impact as we would like to see. Now, that's why we thought RAGE might be important, and I show you some animal data that really supports this. But as James already alluded to, RAGE is involved in a lot of these inflammatory pathways, and these are not only relevant for asthma on the right, they're also relevant for COPD and even cystic fibrosis, on the left, and associated with multiple different interleukins and cytokines, and also in COPD neutrophilic inflammation, which is important to really attack that the current biologics are not really fulfilling. Now, RAGE is also necessary for T2 high. So I, I want to make the case that RAGE is really not only for T2 low, but also for T2 high. You see, on the left in these bar diagrams with house dust mites and Alternaria, eosinophilic inflammation in animal models that RAGE knockouts take these responses very far down to almost eliminate them. And there is a schematic on the right. So RAGE can work for T2 high or should work for T2 high. And what's shown here, it also works for T2 low. Importantly, on the left, if there is an Alternaria model that drives out neutrophil inflammation into the airway, which is not depicted here, humoral responses are still intact, and also IL-4 that was already seen on the slide by James, is not affected by RAGE knockout. On the other hand, on the right, a lot of the inflammatory pathways into T2 low inflammation are basically completely blocked under these conditions. So RAGE is the inflammatory center that is important for T2 low as well as T2 high inflammation. Now, if we think about neutrophilic inflammation, we also think about COPD. As mentioned before, when you look into the left upper corner, there is a slide with a large expression of the mucins in the airway epithelium. This is driven, as shown on the right in the schematic, by epithelial damage that creates a specific IL-33, namely oxidized, that seems to drive this inflammation specifically through RAGE. What you see is that if you do the anti-IL-33, that's just a proof of concept, you can reduce significantly the inflammation and the overproduction of mucus. What you see on these bar graphs on the right, RAGE, which is on the bottom right bar graph, anti-RAGE, is as effective as anti-IL-3 in reducing this inflammation. So the hope that COPD could be targeted as well with an effective treatment of RAGE, meaning the inactivation of RAGE. Now, RAGE is also necessary for sustained signaling. So on the left, you see a schematic that shows you again how inflammation and mucus production is actually driven by RAGE, and it requires STAT6. But if you knock out RAGE, you will lose the STAT6 signaling and thereby the sustained inflammation in these airway epithelia. And so if you think about that, even if a stimulus were to create a short activation of inflammation, it will not be sustained with effective blockage of the RAGE signaling pathways. Now, this sounded all fairly straightforward, but you can see that there are a lot of molecules in the airway that we call RAGE ligands. They were briefly discussed already by James, but they can activate a myriad of inflammatory responses. And so they all bind to RAGE and activate it. And so if we think about all these that are present in inflammation and also asthma and COPD, blocking the RAGE signaling pathway should take care of multiple ones of those, the S100s and HMGB1, for instance, as an example. And so it is a very effective way of blocking the initiation and to sustainability of inflammation in the airway. Now, briefly, I wanted to talk about biomarkers that we're using, especially in asthma and what you also saw in COPD sometimes, because these medications that the biologics work mostly in T2 high inflammation, and in COPD, some of that is the case as well, but in less than 30% of the patients. So exhaled nitric oxide has been used very extensively in an effort to see whether we have T2 high inflammation or T2 low inflammation, and whether or not we expect treatment having efficacy, and then also following the exhaled nitric oxide. What you see, however, in that table below, is that the specificity and sensitivity of FeNO to predict eosinophilia is moderate, and I mean, it's not a great biomarker. And despite some people having come up with fairly elaborate and sophisticated treatment guidelines of how to use FeNO, especially in asthma, to say, if you have over 50 parts per billion, there is T2 inflammation, well, that's likely, it's not certain. However, the asthma probably responds to inhaled glucocorticosteroids, and if it's low, you don't really know where you are. So the guidelines that I'm showing here have been really received with mixed results, and we have to be careful how we use the interpretation of FeNO, especially in the treatment success. Now, when you look here, is that baseline FeNO has not been very useful in assessing the reduction, this is on the left graph, in acute exacerbations rate over 52 weeks, at least for the IL-5 therapies in biologics. You see there a wide range of FeNO and has about the same reduction in the exacerbation rates. On the other hand, for tezepelumab and dupilumab, the initial FeNO levels. High FeNO levels have been predictive, at least somewhat predictive, of how the response to therapy will be. Surprisingly, the FeNO reduction, however, during treatment, is not necessarily predictive of the exacerbation rate decreases. And this is likely because of all these different interleukins and how they're influenced by the therapies. But you see here that blood eosinophil reduction and FeNO reduction are not always in parallel, and so you can make a little schematic of how that really works. More importantly, if you look at dupilumab and tezepelumab, the FeNO change over time, and this is both 52 weeks. On the left, you see a reduction towards the left and an increase towards the right, and while there's some correlation with exacerbation rate, the correlation is overlapping with placebo, and that is not gonna be very, very good as a decision maker in terms of response rates. For tezepelumab, you see that the changes are not at all predictive of the exacerbation rate. So I think that's important to think about biomarkers and how we really use them in decision-making of therapies. So in summary, in asthma therapy, there is still an unmet need. Even in T2 high asthma, there is not an optimal response to the biologics. T2 low, especially, has basically no real therapy that is influential. RAGE is an opportunity to target the inflammatory pathways for both T2 low and T2 high, and it's not only in asthma important, but potentially important in many other airway diseases, including COPD and potentially cystic fibrosis as well. Assessing therapies and how we should start in terms of biomarkers in the asthma, in particular, many of those or all of them have limited value. And while the initial FeNO level might be potentially useful to assess T2 high responsiveness, the changes in FeNO over treatment are not correlated to the reduction in exacerbations, which are the most important real outcome in asthma therapy, obviously. And therefore, efficacy is difficult because you have to do long-term clinical trials to actually look at the decreases in exacerbation. And unfortunately, we don't really have a good biomarker yet for predicting the long-term success. With that, I'll give it over to John. Great. Thank you for that overview, Matthias. So I'm going to provide an overview of our three ongoing first-in-human studies. The first being an overview of ARO-RAGE. And I'm going to subdivide the ARO-RAGE study into two parts. This is a summary of the initial design of the ARO-RAGE study. In this initial part of the study, we evaluate ARO-RAGE as a single dose or as multiple doses given to healthy volunteers or NHPs in this schematic. Multiple doses in this study constituted two total doses, separated by one month. And we dose range between 10 mg and 184 mg. The study then proceeded into cohorts of patients with mild to moderate asthma, to whom we also gave two total doses. The dose levels between 44 mg and 184 mg. This portion of the study has now been fully enrolled, and the key objectives of this portion of the study were to understand dose-ranging effects on safety, as well as effects on target engagement, using soluble RAGE protein as our biomarker of target engagement. Okay, first, to briefly go over some of our safety data. ARO-RAGE has shown a favorable safety profile to date. I've broken this down into five domains here, and I'll go through each very quickly. In terms of adverse events, there have been no treatment-related SAEs in this study. There have been no adverse events considered to be severe, and no subjects have had to withdraw from the study or discontinue study therapy due to any adverse events. We followed lung function over time in the form of spirometry and diffusing capacity and haven't seen any patterns of adverse changes. We've evaluated inflammatory cell counts and differentials in BAL fluid from healthy volunteers and haven't seen any pro-inflammatory effects after study drug administration in those subjects. We've looked at chest X-rays and have seen no abnormal chest X-rays following dosing in any study subjects. We've looked at a range of safety labs and have not seen any patterns of adverse changes. So we've been quite pleased with the safety profile to date. In terms of target engagement, as James mentioned before, our biomarker of target engagement was designed to be in line with a localized geography of RAGE expression in the distal lung. So we're measuring soluble RAGE protein, which we're measuring in both airway samples, so bronchoalveolar lavage or BAL samples, as well as serum samples that integrate what's happening over the entire lung. Over the next three slides, I'll be reviewing some of the data that we presented at the American Thoracic Society conference this May of 2024. This slide provides an overview of the effects of ARO-RAGE on RAGE silencing in the airway by looking at BAL samples of soluble RAGE in healthy volunteers. On the left, we're showing the dose-ranging effects of ARO-RAGE therapy on soluble RAGE levels in BALF in healthy volunteers who have received a single dose of drug. The follow-up bronchoscopy here is at a time point of one month after that single dose. In this context, we see that at the highest dose level of 184 mg, we have a 90% decrease from baseline in soluble RAGE in the airway. Moving over to the right, this data shows the effects of 184 mg when given as two total doses, again, to healthy volunteers. Here, following two doses, we have near complete depletion of soluble RAGE from the airway to the order of 94% mean decrease from baseline at a time point of one month following the final dose, with sustained deep silencing at a time point two months following the final dose. Unfortunately, we are able to pick up and measure airway depletion of RAGE expression with a blood biomarker in the form of serum measurements of soluble RAGE. So here I am showing the data again from healthy volunteers. On the left, looking at healthy volunteers who have received a single dose of ARO-RAGE on day one, and on the right, healthy volunteers who have received two total doses of ARO-RAGE. I'm looking at the effects on serum soluble RAGE over time. Again, we see a nice dose response, where at the highest dose level of 184 mg when given twice, we achieve a deep mean reduction of 88% in serum soluble RAGE at the time of nadir, which is at day 57 or one month following the final dose, with a slow return to baseline over time. When looking at all healthy volunteer subjects, we have seen a maximal silencing of 96% decrease from baseline among healthy volunteer subjects who have received ARO-RAGE therapy. All right, this slide... Sorry. is now looking at the effect of ARO-RAGE upon soluble RAGE in the initial asthma cohorts. The C1 through C3 cohorts shown on the following study schema. What we're doing here is we're comparing the effects of the drug in healthy volunteers and in asthma patients who have received the same dose regimen. These are either subjects, healthy or asthma, who have received two total doses of drug at dose levels of either 44 mg, 92 mg or 184 mg. The comparison here is looking at the effects on the mean maximum serum soluble RAGE reduction following these two doses. I think the overarching message here is that we're also achieving deep RAGE silencing in asthma patients, with a similar effect profile on the asthma patients that we're seeing in the healthy volunteers. At the highest dose level of 184 mg, we're seeing a mean maximal serum sRAGE reduction of 77% in the asthma patients. And among all asthma patients, we've seen a maximal reduction of 88% from baseline in serum soluble RAGE. Integrating all of the data from both healthy volunteer subjects and asthma subjects, our pharmacology team has built a model of sRAGE reductions over time and investigated different dosing regimens. And what is clear from that model is that we think that we are able to move forward into later phase studies, dosing ARO-RAGE as one dose every two months, with subsequent deep depletion of RAGE expression over time using that dosing regimen. Okay, so that provides an overview of the initial portion of the study. This now is an overview of the addition to the study or part two of this study, which we're calling the high FeNO portion of the study. In the high FeNO portion of the study, we're enrolling patients with asthma, who, as Matthias covered before, have a biomarker of increased airway inflammation in the form of elevated FeNO or increased nitric oxide in the airway. These patients also need to be on a stable maintenance dose of inhaled corticosteroids and are allowed to have more severe airflow limitation than in the earlier mild to moderate asthma cohorts. In these high FeNO cohorts, based on the results from the initial asthma cohorts, we're investigating dose levels between 92 mg and 184 mg, because we think that is the dosing range that we're likely to carry forward into future phase II studies. These cohorts are actively enrolling, so there's no data readout that I have to share with you today. But I did want to give you a sense of how we're thinking about these eventual data in terms of decision-making for the ongoing development program. The impetus behind adding these high FeNO cohorts was we took a look at the data from the initial cohorts in the study, saw clear evidence of target engagement, saw a benign safety profile, and based on our belief in RAGE as a target, knew that we wanted to move forward with a phase II study for ARO-RAGE. Phase II studies take time to start up, and we asked ourselves: Well, what can we learn in parallel with start up of phase II via an expansion or an extension of the ARO-RAGE 1001 study? And thinking about that, we decided that we could try to learn two things. The first was, again, now that we think that we're going to be operating in this dosing range of 90 mg- 180 mg, we wanted to fill in a gap and to investigate a, a dose in between those of 120 mg. So we added that dose level to the high FeNO cohorts, and as these cohorts have been somewhat slow to enroll, we've since also added that dose level to the healthy volunteer cohorts. Secondly, and I think more importantly, we wanted to see if we could extend the findings from target engagement to findings informing on the potential anti-inflammatory effect of ARO-RAGE in the airway. As Matthias covered nicely before, there is no single really ideal biomarker of airway inflammation, but FeNO is a biomarker that I think has been commonly used in prior clinical studies, and that is easy to investigate in the context of a clinical study program. On the right is a summary of how we are thinking about the eventual FeNO data that's going to come out of these cohorts. In the center here, again, we have a diagram of the various inflammatory mediators that in animal models have been shown to be downstream of RAGE signaling. And I think the two key points to take from this are, one of the inflammatory mediators that is downstream of RAGE signaling has been IL-13. IL-13 is the primary cytokine that's been shown to increase nitric oxide levels in the airway and to upregulate FeNO. So the thought is that by silencing RAGE in the airway, we could decrease IL-13 and thereby decrease FeNO. One corollary of this diagram or another point to take home from this diagram is that, as James and Matthias covered before, RAGE is expected to have broad anti-inflammatory effects in the airway, on pathways that are outside of the IL-13 pathway. So one thing to, I think, recognize is that FeNO is a good readout on IL-13, but it may not read out on the broader anti-inflammatory effects on other pathways, both Type 2 pathways or pathways more relevant to neutrophilic inflammation. The other thing that we're cognizant of, looking at prior biologic studies that have incorporated FeNO, is that the effect of a drug on FeNO is not necessarily predictive of the clinical efficacy of an asthma therapy. I'll hit three points that I think Matthias already touched on, when that I think clearly illuminate that. The first is that there are drugs that have gone through clinical development that decrease FeNO very well, but that then didn't actually work as asthma therapies. The IL-13 monoclonal antibodies are a good example of that. Conversely, there are drugs that work very well as asthma therapies, but they don't decrease FeNO very well because they're working on pathways outside of the IL-13 pathway. As Matthias, I think, reviewed before, the IL-5 monoclonal antibodies are a good, good example of that. Finally, for drugs that do reduce FeNO, drugs like dupilumab and tezepelumab, what's become clear over the past year is that a patient's FeNO response is not associated with their asthma exacerbation response. So if a patient on tezepelumab has a large decrease in FeNO, that actually is not predictive of whether or not they'll actually clinically respond to tezepelumab therapy in terms of having a decreased exacerbation rate. So we view FeNO as a translational readout on the effects of IL-13 in the airway, but we're cognizant of the fact that the FeNO effect doesn't really give us confidence or tell us with confidence whether ARO-RAGE will be efficacious as an asthma therapy. To understand that, we think that we really need to move forward with a phase II study that's designed to inform on whether ARO-RAGE actually results in clinical control of asthma. And this is what we think that, or what we are planning that study to look like. So this is an overview of the planned ARO-RAGE 2001 phase II- A study. The patient population that we plan to evaluate in this study is going to be a severe asthma patient population. So these are patients who are on background ICS and LABA inhaler therapies and yet remain uncontrolled on that background therapy. So this would be a patient population that looks very similar to the patient population investigated in many of the later phase biologic studies. Consonant with the idea that ARO-RAGE is that silencing RAGE should have broad anti-inflammatory effects in the airway, we don't plan to limit this study to patients with, say, an elevated blood eosinophil count. Rather, we plan to take all severe asthma patients and to enroll roughly 50% of the patients who have markers of Type 2 high inflammation and 50% of patients who have markers of Type 2 low inflammation. Excuse me. The key outcome of this study, again, is for severe asthma patients who are uncontrolled on therapy to understand if ARO-RAGE then brings their asthma under control, whether it prevents asthma worsening events. To measure that, we'll be looking at a composite of severe exacerbations in milder asthma loss of control events, and this will be a composite that is in line with, you know, composite endpoints that have been used in recent asthma phase II studies. Of course, we'll also be very interested in lung function, looking at FEV1, and in looking at patient-reported outcomes that capture asthma symptoms, asthma control, and asthma-related quality of life. In order to understand whether ARO-RAGE can control asthma, we're going to need to have patients on study, for a longer period of time and to look at more patients than we did in the ARO-RAGE 1001 program. So we anticipate this being roughly 250 subjects on study for approximately half a year. And again, what we hope to learn from the ARO-RAGE 2001 study is to do a proof of concept study in our target patient population to really understand what ARO-RAGE's effects are on asthma control, asthma exacerbations, lung function, and asthma-related symptoms. And we think that a positive result from this study would really then provide high confidence that ARO-RAGE could be a therapy that would potentially be successful in a late-phase asthma development program. Okay, so as a brief overview, sorry, let me advance here of what I just went over. ARO-RAGE has been safe and well tolerated to date at all dose levels. It's shown evidence of deep and durable target engagement, which should enable every two-month dosing in future studies. We continue to enroll patients into the high FeNO asthma cohorts and are awaiting a data readout from those cohorts. Those cohorts are interesting to us as a translational readout of effect on IL-13-related inflammation, but we don't expect the FeNO results to predict the eventual clinical efficacy of the drug. And to understand that, we are planning a phase II study to evaluate the effects of ARO-RAGE on asthma control, and we plan to start that study up in parallel with the completion of the high FeNO cohorts. Moving on to the other two drugs, I'm going to provide a much briefer overview of ARO-MMP7 and ARO-MUC5AC. These two studies are still enrolling patients actively into the patient cohorts, and for both of these studies, as James covered before, it's really the patient cohorts that are going to be highly informative in terms of target engagement. So I'll provide here an overview of where we are in the overall study conduct. For ARO-MMP7, to date, we have fully enrolled all of the healthy volunteer cohorts. We have now moved on to the IPF cohorts. IPF cohorts in this study, or subjects in this study received three total doses, separated by two-week intervals. We are currently enrolling the first IPF cohort, cohort C1, at a dose level of 116 mg. As James covered before, our biomarker for this study is measuring MMP-7 protein, and the location of biomarker measurement is aligned with the location of MMP-7 overexpression in the distal airway. We will be measuring MMP-7 protein in BAL samples in IPF patients, as well as serum samples, which again, integrate what's happening over the entire airway. For ARO-MUC5AC, we have to date, dosed healthy volunteers through all dose levels, inclusive of 232 mg. We have moved on, to the patient portion of the study, which is enrolling both asthma patients and COPD patients. Patients in this study, as with ARO-MMP7, are receiving three total doses at two-week intervals. In the asthma patient portion of the study, we have nearly completed the 108 mg cohort. In the COPD portion of the study, we're still enrolling patients in the 56 mg cohort. As before, biomarkers of target engagement in this study are aligned with the regional overexpression of MUC5AC in patients with muco-obstructive disease. Unlike RAGE and MMP-7, which are secreted into the systemic circulation, MUC5AC is retained within the airway, and so we're focused on airway samples as a readout of target engagement. So in this study, we're collecting induced sputum samples from all of our patient cohorts, and then putting those induced sputum samples through a mass spec-based assay to measure MUC5AC protein levels. So we look forward to informing you of updates on target engagement readouts and safety readouts from the patient cohorts once they're complete. And with that, I will turn things back over to Vince. Thank you, John, and thank you, Matthias and James, as well. So I just wanna... Oops, it's not switching. Sorry. Okay. I just wanna go, you know, we, we've gotten very technical, today about the pathways and about the clinical studies and about measurement. So I wanna kinda level set. You know, what, what are we, what are we trying to do here, broadly, with the Arrowhead pulmonary platform, and then each of the products, in particular? And so, you know, this is a, a good chart, about where we see potential opportunities to help with patients with, with unmet need. And I like to categorize this, kind of in these three, three different columns. We're looking at across the pulmonary platform, we're looking at addressing three of the primary causes of chronic lung disease, and that would be inflammation, mucus obstruction or mucus hypersecretion, and then fibrosis or interstitial lung disease. And you see that we're covering many different diseases that are characterized by those different, you know, those different pathways. So for ARO-RAGE, we see potential for it being addressing asthma, COPD, and as the folks before mentioned, potentially cystic fibrosis. I think that one thing that we covered today that we haven't talked about before, and we certainly haven't shown any of our preclinical data before, is that the potential for that RAGE pathway to be active for Type 2 inflammation as well as for neutrophilic inflammation. So there's a lot of opportunity and unmet need in these diseases for these inflammatory process diseases. For MUC5AC, there's gonna be some overlap between potential patient populations. But for MUC5AC, for diseases that are characterized by mucus hypersecretion, we think that MUC5AC has a lot of potential in several different disease areas. We talk a lot about asthma and COPD, but we do see potential for CF, for non-CF bronchiectasis, and then primary ciliary dyskinesia. We haven't talked specifically about what the plans are for future clinical studies there. I think we're most focused on establishing target engagement and safety in the current clinical studies. And then, you know, next year, we will likely talk more about where we're taking this. And then lastly, for ARO-MMP7, there are really no great options for patients with IPF. There's been a lot of development, but it's just it is an area where patients are in dire need of new therapies. And we think that our preclinical data for ARO-MMP7 are very compelling and show, you know, great potential for that product. So where are we? And I'll talk about each program in particular, and what can you anticipate for upcoming milestones for the programs? So for ARO-RAGE, you know, we mentioned that we are in that design and planning phase for a phase II study. We plan on having regulatory interactions about the phase II design in the second half of this year. You know, John talked about this, but I think it's, you know, bears repeating, that we initially decided to do the high FeNO cohorts because we had some time. We had six months or so before we really could start a phase II study, and so we went back and thought, "What else can we learn?" And one we could learn, we can add another point in the dose-response curve. It seems clear from healthy volunteers and from the initial asthma patients that between 92 mg and 184 mg, there is a dose-response. You know, a modest dose-response, but we feel like 184 mg is getting near complete suppression of lung expression of RAGE. But we don't know the midpoint there, and so we decided that we would like to find out what 120 mg does? Is that the top of the dose-response curve? Is there a reason to continue to dose up to 184 mg? And so the high FeNO cohort have one dose cohort looking at 120 mg, and we've also added a 120 mg cohort in the healthy volunteers, so we can fill in that you know that spot. And so, you know, we get this question very frequently: What is the high FeNO cohort going to show us? And this is a totally unsatisfying answer, but I think Matthias and John, you know, both showed clearly that we don't know. You know, we don't know if FeNO is really predictive of an end clinical benefit in these patients. It's just a biomarker of a biomarker. And so we still think it's valuable, and so we'll continue to do that study, but it is not gating for the phase II. You know, we have clearly established, I think, that we're getting a very high level of RAGE suppression in the lung. And so now the next step is go into a phase II, and see if we can get asthma control and reduce exacerbations. And again, as I mentioned, you know, we think that there's an opportunity there for Type 2 inflammation as well as for neutrophilic inflammation with that particular target. So, a phase II, we're hoping that we can get that started, in the first half of 2025, and somewhere around the same time, we hope to have the high FeNO cohorts completed. So moving on to ARO-MUC5AC. So we are enrolling the patient cohorts. Our hope is that we'll have a top-line readout for target engagement, safety, and tolerability in the first half of 2025. And then we'll move into the same process where we are right now for ARO-RAGE, which is design a phase II and plan a phase II and start those regulatory interactions, all in the first half of 2025. MMP-7 is at basically the same stage. We need the patient data in order to identify a dose and potentially a dose interval. You know, we need patients who express that the cell type or have the cell type that expresses MMP-7 to identify target engagement. And then we'll move on to phase II design and planning as well in the first half of 2025. Okay, so let me take a moment. I'll compile some of the questions and I will ask those to the panel. Just give me one moment, please. Okay, our first question is for Dr. Salathe. And this is... Sorry. Can you discuss the potential risk of blocking RAGE signaling, as well as your take on the safety generated so far in the ARO-RAGE program? Well, so the questions are whether RAGE silencing has any risks to it, and that question is fairly straightforward. So far, there is no certainty that this has actually any bad effects. The worry are sometimes the infections, but number one, this has not been shown to be an issue, even in sepsis models of at least adult animals. Obviously, we don't know that for human beings, but it is, however, shown in newborn mice, I believe, I remember that, that that has a bad effect on infections, but not in adult animals. So. And these are knockouts, and therefore, that by itself, I wouldn't think this is actually an issue. In sepsis model, in fact, there was a benefit of survival, and that means that your RAGE axis is really, if it's overstimulated, it's actually, it results in negative outcome for you. So that, that's the only thing I can tell you. I also know that, what John presented is that the patients or the normal human subjects that were subjected for a period of time with silencing of RAGE to the degree that you've seen in the slides, didn't have any signs of an issue in terms of side effects or any adverse effects. So that would suggests, that would suggest, in combination, that there is no, no knowledge on really risks of silencing, RAGE at this point in time. Thank you. I make one more comment. You know, we're using a lot of immunosuppressive medications, you know, even, even during COVID, et cetera. I think if there is a slight risk that came up, that can be managed, right? I mean, I don't say this will be never happening, but, you know, we're using a lot of these medications, and if they're required, we can manage that as well. But there is no sign of that happening. Thank you. So our next question comes from Jason Gerberry at Bank of America. This is also for Dr. Salathe: Can you discuss the bar for ARO-RAGE clinical efficacy in Type 2 asthma needed to displace the established biologics versus what would relegate ARO-RAGE to biologic-refractory setting? Oh, the bar? I don't know whether I can answer the question of the bar. And as you've seen, there is still room in, even in T2 high, asthma for improvement. So it really depends on what the phase II, and then later trials will show in exacerbation reductions and true full remissions. As you've seen, even in biologics currently, there is about a full remission of about 35%, in the best case scenario, 39%. That leaves still a lot of room. So under the assumption, and, you know, this is a huge assumption, that the RAGE pathway influences more inflammatory pieces of the airway inflammation in asthma, and it can be effectively blocked, you would expect that this is potentially better. If it's not fully blocked, and that's the other question, then we will see. In T2 low, there is clearly really no therapy available that is satisfactory, and there is obviously a huge room, and then in the other diseases, as already discussed. Thank you. And the next question is from Brendan Smith at TD Cowen, and this is likely for John and James. For the phase II study of ARO-RAGE, which patients will be included, and how are you thinking about stratifying them? And would you expect a different level of efficacy in Type 2 high and low? James, do you want me to take that? Yeah, go ahead, John. Yeah. So as you know, mentioned on the prior slide, the idea behind RAGE signaling is that silencing RAGE could have a very broad effect, again, on inflammatory mediators that are relevant to both Type 2 high patients and Type 2 low patients. So the intent would be to evaluate an ARO-RAGE therapy in both of those populations, right? Type 2 high and Type 2 low asthma patients. The stratification plan would be likely to break those populations roughly in half, so that about half of the subjects who enroll into the study had evidence of Type 2 high inflammation via an elevated baseline blood eosinophil count, and about half of those patients had low baseline blood eosinophil count. James, I'm sorry, what was the second part of the question? Would we expect different efficacy in type 2 and low type? Well, type 2 high. Oh, yeah. So again, I think the expectation based on the preclinical data is that there's the possibility of efficacy in both of these populations. I mean, of course, we'll have to carry out the study to learn how the drug performs in those two subpopulations. Certainly, you know, any evidence of efficacy in a Type 2 low population, I think would, as Matthias, you know, indicated before, put the drug on very solid footing, as a, you know, potential asthma therapy to address an unmet need, that really remains given what the current therapies can accomplish. Thank you. And actually, this next question from Mayank Mamtani at B. Riley is somewhat associated with that, and this is for Matthias. Can you touch on... Actually, I'll paraphrase. He's asking about where tezepelumab and dupilumab sit in that cascade, and does RAGE sit upstream of that? And if so, how does that inform how ARO-RAGE may perform in the clinic, in asthma control, I would say. All right. So yes, RAGE is upstream of TSLP and obviously the other inflammatory pathways as well. So it is the most upstream, I guess, receptor and inflammatory cascade molecule that we know of, or that I know of. Now, that would indicate that you can block more than what you block currently with the biologics. Having said that, right, it all depends how much we can block it. And that's the clinical question that we need to establish in clinical trials. But theoretically, the answer is yes. It's upstream, therefore, potentially better. Thank you. So our next question is from Maury Raycroft at Jefferies, and this is probably for John. ARO-RAGE phase II study, will it be, will it be placebo-controlled, and what will it be powered to show, or what will you need to achieve in order to justify moving forward with more development? Yeah. So, so I, I don't wanna, I guess, get into too much detail, at the current time, as the study is still, you know, under development, and there will need to be regulatory interactions. I mean, briefly, I can say, that yes, the, the study will be placebo-controlled. And in terms of powering, you know, we're going to power it to give us a clear readout on a significant reduction, in asthma loss of control events. And it'll be powered, very similarly to how other, studies that have used similar composite endpoints have been powered, for, for phase II studies in, in asthma. So I'll, I'll leave it at that. Thank you. Next question is from Ellie Merle at UBS, and this is for the Arrowhead team. How are we thinking about prioritizing ARO-RAGE versus ARO-MUC5AC in COPD? Yeah, I'll take that one. So we're still waiting to see biomarker data in COPD patients with the ARO-MUC5AC. So I think a lot... That answer depends on how those data look. Of course, we've completed the study with ARO-RAGE in the healthy volunteers, and then some of the patient cohorts are ongoing, and we know we can get good knockdown of that target in both the healthies and the patient populations. But in terms of prioritization, I think we still need to get the biomarker data from the MUC5AC COPD patient cohorts to kind of make a call on prioritization. Thanks. I think we have time for one or two more questions. Wait, I have a question from Maury Raycroft at Jefferies. This is likely for James or possibly David. Why do you need higher doses for MMP7 and MUC5AC versus RAGE? And with the broad effects on RAGE, could there be any safety risk? And that, actually, that second part, Matthias covered that earlier on. So why does the platform need different doses for different targets? Yeah, I think that's a factor of both the target, but also the sequence. And there are some sequences that are more potent than others, and there are some targets that are easier to knock down than others. And we've seen that with our liver targets, that you know, there are targets like alpha-1 antitrypsin or or TTR or apolipoprotein C-III, that seem to be very amenable to an siRNA knockdown approach. Lp is another one, and you can get really great knockdown with a low dose. I think that, again, that's partially target dependent, but also dependent on just finding a potent sequence. Likewise, there are other targets, maybe like ANGPTL3, that require a higher dose to achieve maximum knockdown. And I think that's the difference with the differences of RAGE versus MMP7. That RAGE trigger is uniquely potent. The chemistry between the two are the same. So, you know, the backbone modification patterns and all that, that sort of thing, are really the same between RAGE and MMP7. And it may also have to do with just the difficulty of silencing the sequence, and that may be due to, you know, mRNA's secondary structure or other things that make it more challenging to target with an RNAi approach. So I think that's the best answer I can give. I don't know, David, if you have any other thoughts on that. Yes. My other thoughts also is about the expression of the transcript in the lung. So luckily, you know, the RAGE is highly expressed in the lung, so makes much easier to look for that knockdown for something that's more rare, you know? And that also contributes for the need of the high dose. Yep. That, that's a good additional point. And, and we've seen that with the, the liver programs also. The targets that have a lot of expression, again, some of the examples that I, I listed are easier to silence than, than targets with kind of low or sporadic expression. Thank you. Okay, this will be our last question, and actually, this was asked by a couple, couple different folks. So for ARO-MMP7, are we planning on studying that as single agent or in combination with standard of care, either in the phase I or beyond? And are we looking for IPF patients who are stable but insufficiently managed on current standard of care? Do you want to take that, John? Yeah, sure. I guess first I'll address that in the context of the 1001 study, and then more broadly. In 1001, we're allowing IPF patients who are either on or not on concomitant anti-fibrotic therapies. They could be on pirfenidone or nintedanib or not. And again, the real purpose of that study is to understand target engagement, and we think that we can understand that in the presence or absence of the concomitant therapies, as there is not clear evidence that those therapies are really impacting the MMP-7 pathway. More broadly, thinking forward into later phase programs, you know, I, I think that the field is anticipating that, you know, IPF is a disease that's driven by multiple pathways in the lung, and that is probably going to be a disease state that responds to combination therapies. So we would anticipate in later phase studies, studying ARO-MMP7, either in patients who are on background IPF therapies or, or, again, on patients who are not on backgrounds. And, and that's very similar, I think, to the late phase development programs for other drugs that are currently in phase II or phase III studies. They, they take all comers, whether they're on anti-fibrotic therapies or not. Thanks, John. And actually, we have one last question that came in from Luca Issi at RBC, and he's asking about our business development plans broadly for pulmonary, and for each individual target. So I'll take that. So I think that, you know, our stance in the past for pulmonary has been that we really didn't want to have any kind of partnering discussions. We felt like these first initial programs, we wanted to get proof of concept, for, one, the platform, and then, two, individual products. And with the platform, you know, proof of concept can come in a few different... It's a spectrum. I would say a few different points get us confident that the platform is doing what it's designed to do. You know, first, pre-clinically, we need to establish acute safety in acute toxicology studies, and we've kind of checked that box. Second, we need to establish safety and tolerability in healthy volunteers. Third, we want to establish safety, tolerability in a patient population. You know, fourth, I'm gonna miss the numbers here, so I'll just say, go, go. Moving on, we want to establish target engagement in whatever population we can. So with RAGE, that first took the form of healthy volunteers. Next, it took the form of asthma, mild to moderate asthma patients. And again, we've checked those boxes. Next, you want to establish chronic toxicology. And you know, we mentioned this on a conference call, one of our last or two earnings calls ago, is that we've completed chronic toxicology studies for two of the three programs, and the third will come shortly, showing that we can, you know, we should be able to dose at the, with the interval that we want and at an active dose. And so that's kind of what you always want to learn for a new platform initially. Does the platform translate? The results that you saw pre-clinically, do they translate into healthy volunteers, and does that translate into a patient population? And so I think that we've kind of checked that box pretty broadly with RAGE and shortly with the other two programs. And so with respect to business development or partnering-... You know, I think that we are more open to those discussions at this point. You know, that doesn't. It's not a change in our strategy. It's just we feel more confident that the platform in the clinical study is doing what we expect it to do. And now the next step is not target engagement, but with RAGE, specifically, to establish efficacy, and that's in a phase II study. As we mentioned, we're looking at asthma control and reduction of exacerbations in a phase II study. And that's a big step. That's not just, is the platform doing what it's designed to do? And is the product inhibiting the target that it was designed to inhibit? That is, is there an opportunity? Is it filling a need that doesn't exist? And that's a big step up. So, you know, this is, you know, my answer about business development is not that our strategy is changing, it's that we feel more confident that we know what we have here. And so if there are discussions on business development, we are more interested in having them than we were in the past. But again, you know, that doesn't mean that these assets are up for sale, but we would be willing to have discussions, when in the past, we weren't. So that is the last question we have time for. So I wanna thank everybody for joining us today at home. And I wanna particularly thank Matthias. It was very helpful for you to go through your presentation, and for James and John for the presentation, and David for helping us with the panel. We will see you all in about a month for our next R&D event webinar. Thanks so much!