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

Good afternoon, and welcome to the Arrowhead Summer Series of R&D Webinars Part 3. [Operator Instructions] 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 want to let everyone know we will be making forward-looking statements today, so please refer to our SEC filings for risk factors. So 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. So 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 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 position perspective on the disease areas and the targets that we're working on. And 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 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 overview. James Hamilton, our Chief of Discovery & 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 is Head of Clinical Development for Pulmonary. Dr. 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 want to quickly introduce Dr. Salathe. He has been one of our advisers 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, 4 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, 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 nondilutive 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. 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 going to focus on these 3 programs: ARO-RAGE, ARO-MUC5AC and ARO-MMP7. These are our first 3 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, our 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, and we do use a different targeting ligand, specifically a small molecule targeting in 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 nonclinical experience. And we've learned that the platform is most efficient at delivering siRNA into 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 range, 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 pleiotropic, and the inflammatory pathways that it works through involve multiple different both type 2 and non-type 2 cytokines. So 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. And 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. And 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, as 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 MMP2, MMP9 and MMP12, 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 MMP7, which is overexpressed in the idiopathic pulmonary fibrosis lung and is a prognostic marker in IPF. MMP7 is secreted by the aberrant basaloid epithelial cells, and this is a cell type that is unique to the IPF lung. The secreted MMP7 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 MMP7, so it's really an ideal target for this platform. And as we've stated previously, MMP7 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 MMP7 from the healthy volunteer cohorts. However, in the IPF patient cohorts, the increased MMP7 expression is coming from the deep lung aberrant basaloid cells, and we should be able to measure decreases in MMP7 in IPF patients using BALF and blood samples. Moving on to the third program. This is ARO-MUC5AC, which targets goblet cell expression of mucin 5AC, 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 bronchials, leading to small airway muco-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 -- in the disease that was mentioned before, COPD, in particular. So when we think about asthma first, we have 2 main sources of inflammation. One is T2-low asthma, and the other one is T2-high asthma. And most biologics, actually, really, and I showed more data on this, are treating T2-high asthma. That's true for all of the ones on the market. And rather, they have been used in T2-low asthma, as you're going to see, there is not as much efficacy of these biologics in this space. So you see here a 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's still a lot of room to improve for full remission, at least in the severe asthma types. If 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%. And so 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 a 20% to 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 into T2-high asthma. If you look at here at the plots, to the left, tezepelumab, I'm always having trouble with this word, and 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. And 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 by 39%. So again, showing that even in T2-high, there is more room to go. But in T2-low, these biologics, even the best on 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 are 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 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, IL4, 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 in the 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. And 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, and this is driven, as shown on the right in the schematic, by epithelial damage that creates a specific IL-33, and then we oxidized. That seems to drive this inflammation, specifically, through RAGE. And what you see that if you do the anti-IL33, that's just a proof of concept, you can reduce significantly the inflammation and the overproduction of mucus. And 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 if activated. 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, 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 gluco -- corticosteroids. And if it's low, you don't really know where you are. And 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 production. This is on the left graph in acute exacerbation 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 rate. On the other hand, for tezepelumab and dupilumab, the initial FeNO levels, T2 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 are 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 is some correlation with exacerbation rate, the correlation is overlapping with placebo, and that is not going to be very good as a decision-maker in terms of response rates. But tezepelumab, you see that the changes are not at all predictive of the exacerbation. 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.

Right. Thank you for that overview, Matthias. So I'm going to provide an overview of our 3 ongoing first-in-human studies, the first being an overview of ARO-RAGE. And I'm going to subdivide the ARO-RAGE study into 2 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 NHVs in this schematic. Multiple doses in this study constituted 2 total doses separated by 1 month, and we dose ranged between 10 milligrams and 184 milligrams. The study then proceeded into cohorts of patients with mild to moderate asthma, to whom we also gave 2 total doses, the dose levels between 44 milligrams and 184 milligrams. 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 5 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 this study or discontinued 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. And 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 localized geography of RAGE expression in the distal lung. So we're measuring soluble RAGE protein, which we are 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 3 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. And the follow-up bronchoscopy here is at a time point of 1 month after that single dose. In this context, we see that at the high dose level of 184 milligrams, 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 milligrams when given as 2 total doses, again, to healthy volunteers. Here, following 2 doses, we have a near-complete depletion of soluble RAGE from the airway to the order of 94% mean decrease from baseline at a time point of 1 month following the final dose, with sustained deep silencing at a time point of 2 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, a soluble RAGE. So here, I'm 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 1, and on the right, healthy volunteers who have received 2 total doses of ARO-RAGE. I'm looking at the effects on serum soluble RAGE over time. Again, we see a nice dose response. We're at the highest dose level of 184 milligrams, when given twice, we achieved a deep mean reduction of 88% in serum soluble RAGE at the time of gating, which is at day 57 or 1 month following the final dose, within a slow return to baseline over time. When looking at all healthy volunteer subjects, we have seen a maximum 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. So the C1 through C3 cohorts shown on the following study schema. And 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. So these are either subjects of healthier asthma who have received 2 total doses of drug at dose levels of either 44, 92 or 184 milligrams. And the comparison here is looking at the effects on the mean maximum serum soluble RAGE reduction following these 2 doses. I think the overarching message here is that we're also achieving deep RAGE silencing in asthma patients with a similar effect profile of the asthma patients that we're seeing in the healthy volunteers. At the highest dose level of 184 milligrams, we're seeing a mean maximum serum sRAGE reduction of 77% in the asthma patients. And among all asthma patients, we've seen a maximum 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 1 dose every 2 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 2 of the 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 milligrams and 184 milligrams because we think that, 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 a clear evidence of target engagement, saw benign safety profile. And based on our belief in RAGE was the target I knew that we want 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 startup 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 is, again, now that we think that we're going to be operating in this dosing range of 90 to 180 milligrams, we wanted to fill in the gap and to investigate a dose in between those of 120 milligrams. 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, 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. And 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 on in the airway on pathways that are outside of the IL-13 pathway. And so one thing to, I think, recognize is that FeNO, as a good readout of IL-13, 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 3 points that I think Matthias has already touched on when -- that, I think, clearly illuminate that. The first is that there are drugs that have gone through clinical development that decreased 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. And as Matthias, I think, reviewed before, the IL-5 monoclonal antibodies are a good example of that. And 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, it actually is not predictive of whether or not we'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 -- they 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 -- what we are planning that study to look like. So this is an overview of the planned ARO-RAGE 2001 Phase IIa 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. Constant with the idea that ARO-RAGE is that silencing RAGE should have broad anti-inflammatory effects in the airway. We don't plan to let the study to patients with same elevated blood eosinophil count, whether 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 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 effects are in asthma control, plasma exacerbations, lung function in asthma-related symptoms. And we think that a positive result from this study would really provide high confidence that ARO-RAGE could be a therapy that would potentially be successful in 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, has shown evidence of deep and durable target engagement, which should enable every 2-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 2 drugs. I'm going to provide a much briefer overview of ARO-MMP7 and ARO-MUC5AC. These 2 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 the healthy volunteer cohorts. We have now moved on to the IPF cohorts. IPF cohorts in this study or subjects in this study received 3 total doses separated by 2-week intervals. We are currently enrolling the first IPF cohort, Cohort C1, at a dose level of 116 milligrams. As James covered before, our biomarker for this study is measuring MMP7 protein. And the location of biomarker measurement is aligned with the location of MMP7 overexpression in the distal airway. We will be measuring MMP7 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, high dosed healthy volunteers through all dose levels, inclusive of 232 milligrams. 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 MMP7 are receiving 3 total doses at 2-week intervals. In the asthma patient portion of the study, we have nearly completed the 108-milligram cohort. In the COPD portion of the study, we're still enrolling patients in the 56-milligram 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 MMP7, which are secreted into the systemic circulation, MUC5AC is retained within the airway. And so we are focused on airway sales 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 want to -- oops, it's not switching, I'm sorry. Okay. I just want to go -- we've gotten very technical today about the pathways and about the clinical studies and about measurement. So I want to kind of level set what are we trying to do here, broadly, with the Arrowhead pulmonary platform and then each of the products in particular. And so this is a good chart about where we see potential opportunities to help with patients with unmet need. And I'd like to categorize this kind of in these 3 different columns. So we're looking at -- across the pulmonary platform, we're looking at addressing 3 of the primary causes of chronic lung disease, and that would be inflammation, muco-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 pathways. So for ARO-RAGE, we see potential for it be having -- 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 in for -- in these inflammatory process diseases. For MUC5AC, there's going to be some overlap between potential patient populations. But for MUC5AC, which is character -- or for diseases that are characterized by mucus hypersecretion, we think that MUC5AC has a lot of potential in several different disease areas. And we talked 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 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 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, 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. John was -- John talked about this, but I think it's -- it bears repeating that we initially decided to do the high FeNO cohorts because we had some time. We had 6 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 for the initial asthma patients that between 92 milligrams and 184 milligrams, there is a dose response. No modest dose response, but we feel like 184 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 does 120 milligrams do? Is that the top of the dose response curve? Is there a reason to continue to dose up to 184? So the high FeNO cohort have 1 dose cohort looking at 120 milligrams, and we've also added a 120-milligram cohort in the healthy volunteers. So we can fill in that spot. And so 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 both showed clearly that we don't 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, so we will continue to do that study, but it is not gating for the Phase II. 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, we think that there's an opportunity there for type 2 inflammation as well as for neutrophilic inflammation with that particular target. So 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 '25, 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 '25. MMP7 is at basically the same stage. We need the patient data in order to identify a dose and potentially dose interval. We need patients who express the cell type or have the cell type that expresses MMP7 to identify target engagement. And then we'll move on to a 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 so 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 the RAGE access is really, if it's overstimulated, it's actually -- it results in negative outcome for you. So 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 suggest, in combination, that there is no knowledge on, really, risks of silencing RAGE baseline to that.

Thank you.

And I make one more comment. We're using a lot of immunosuppressive medications, 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 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, and 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 biorefractory setting?

Well, there aren't. I don't know -- well, I can't answer the question off the bar. And as you've seen, there is still room, 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 see in biologics, currently, there is about a full remission of about 35%, in the best-case scenario of 39%. That leaves still a lot of room. So under the assumption, and 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, 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. 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?

Yes. Go ahead, John.

Yes. So as 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 is in the full count. And Vince, I'm sorry, what was the second part of the question?

Would we expect different efficacy in type-2 low and high?