Buddy. Thanks so much for coming today. We're here for Arrowhead's Analyst R&D Day, an d we have a lot to cover. I'm just gonna jump in. This is our safe harbor statement. Please refer to the risk factors in our SEC filings. We will be making forward-looking statements in today's presentations. We've got a really good panel, Arrowhead folks, as well as a few external folks who are experts in their d isease areas. We have Michael Benatar from the University of Miami, who'll be talking about ALS and SOD1 specifically. We have Matthias Salathe from University of Kansas, who will be talking about the pulmonary programs, both inflammatory as well as the muco-obstructive program, and Ira Goldberg from NYU, who will be talking about the cardiometabolic. Like I said, there's a lot to cover today. This is the basic flow. We'll go over CNS. We'll go over some of the expansion that we're doing to the TRiM platform to get to new tissue types. We'll have a Q&A session in between each kind of topical area, short Q&A, about 10 minutes. We likely won't be able to cover all the questions. We will have a Q&A session at the end of the day. If you don't get your questions in for the topical areas, just hold them until the end. We'll go into the pulmonary programs. After that, we'll talk about some of the early clinical programs that we have, and then we'll go into cardiometabolic, which will include some data, as well as our strategy for the clinical development and then some of our strategy on the commercial build-out. Then, as I mentioned, we'll have Q&A after that, and then lunch will be available if anybody wants to stick around. Now I'll turn it over to Chris Anzalone, CEO of the company. Thanks. Well, thanks, everyone, and welcome. Just a pointer. There we go. Good. All right. Well, again, welcome. It's great to see all of you here today. We have a saying at Arrowhead that every day matters, and it is an expression of our commitment to patients. You know, every day that we can shave off development time is a day earlier, we can get important medicines to the patients who need them. It's also an expression of our commitment to pushing science and finding new ways to treat patients and to serve patients. I think today is a really good expression and a good representation of these twin commitments. Who are we? I think everyone in this room knows who we are. We are an RNAi therapeutics company with a large pipeline of 12 clinical programs, seven of which are wholly owned, five are partnered. These span from early to mid to late stage clinical programs targeting both rare as well as high prevalence diseases. It's a fast-growing pipeline. We think we can push two to three new drug candidates into the clinic every year. Everything we do is based on the TRiM platform. We have spent an awful lot of time developing this platform. It's a modular platform. We think it enables us to be potentially best in class where we go, and it also allows us to get into new tissue types to follow diseases where they are. Finally, we have the financial resources, I believe, to push these programs to the patients who need them. An important part of our model is partnering. We've got good, strong partners in Amgen, Takeda, Horizon, GSK, and Royalty Pharma, and we anticipate continuing to partner some of our programs. We'll do that judiciously. You know, we will always have a good stable of wholly owned assets. This partnering strategy allows us to bring in non-dilutive capital, as well as to find homes for, you know, those non-core assets of ours. We have a initiative called 20 and 25, where we expect to have 20 individual drug products, either in clinical studies or at market by the year 2025. We're building a different kind of biotech company. As I said, everything we do is based on this TRiM platform that is structurally quite simple. It's composed of targeting ligands, linker chemistries, stabilization chemistries along the backbone of the RNAi trigger, and PK enhancers as necessary. Importantly, we've got libraries of all of these components. It allows us to optimize these candidates. We've created this modular system, this structurally simple system, in order to address multiple cell types, again, to go where diseases are. It also provides a continuity or a confidence in the platform. You know, we've said this in the past a lot, that once we see clinical validation in a certain cell type, we have an expectation of continued success. You know, a cell doesn't care what sequence you're knocking down. Once we see a well-tolerated ability to knock down a gene target, we think we can do it over and over again. Again, it gives us the confidence that future candidates should function as planned, and I think that gives us a greater hit rate than is normal in the industry. Finally, we move quite rapidly from idea to clinic. In the liver, at least, we've been able to go from idea to the clinic in as short as 12 months, and I think we can continue to operate in this fashion, not only with the hepatocyte targets, but also for targets in other tissue types. Has this worked? The short answer is, I think it has. In 2017, we had the TRiM platform, but we had zero drug candidates in clinical studies. Six short years later, by the end of 2023, we will have brought 18 drug candidates into clinical studies. Let that sink in for a second. It is an astonishing accomplishment. In six years, 18 brand-new drug candidates into clinical studies. I don't think that we've seen that in the industry before. These 18 are addressing different cell types. By the end of this year, we will have brought candidates into the clinic addressing hepatocytes, solid tumors, pulmonary, CNS, and skeletal muscle. We are seeing that platform continuity or confidence. Only two of those potential 18 candidates have been discontinued. We're treating many people. We've got over 3,500 people and counting in clinical studies with these drug candidates, and we're moving rapidly. We expect to phase III studies by the end of 2023. Imagine what we can do in the next six years. Today's focus will be as follows. We will have updates on some of our clinical programs, the cardiometabolic, pulmonary, C3, and PNPLA3. We'll also be talking about what's next. That'll be CNS, as well as potential systemic delivery for CNS, and also addressing adipose tissue. Here's our pipeline. We'll be talking about ARO-APOC3 and ARO-ANG3 on the cardiometabolic side. ARO-PNPLA3, our wholly owned NASH drug. ARO-RAGE, the first pulmonary drug that we have data on. We will not be talking about ARO-MMP7. It's too early. We don't have enough data yet there yet. We also will not be talking about ARO-MUC5AC. You know, as some of you may know, that is upregulated by to the tune of around 30-fold in patients, and so it's much easier to study in patients. I expect that we'll have patient data as well as some MMP7 data towards the end of this year. And we'll also be talking about ARO-C3. With that, I'd now like to turn it over to Dr. Benatar. Great. Thanks so much. It's a great pleasure to tell you a little bit about therapy development for SOD1-ALS. These are my disclosures. I do serve as a site investigator for some industry trials and do some advising, consulting around trial design, and my federal and foundation research funding. What is SOD1-ALS? ALS is amyotrophic lateral sclerosis, a neurodegenerative disorder. Mutations in the SOD1 gene were the first described genetic cause of this disease, and overall, they account for around 2% of all patients with ALS. They're found both in patients who have a family history of disease, familial ALS, and also in patients who don't have a family history of disease, what's called sporadic ALS. SOD1-ALS is enormously heterogeneous. There are over 200 different genetic mutations in the SOD1 gene that have been described. In the U.S., one of those, the A4V mutation, accounts for about 50% of all SOD1 cases. There is marked phenotypic heterogeneity across the spectrum. That most common genetic form of SOD1 in the U.S. is very aggressive, with a median survival of 12-15 months, but some of the SOD1 mutations may be associated with survival as long as 20 or 30 years. By and large, mutations in the SOD1 gene produce a toxic gain of function. Although the initial thinking when this was first discovered is that this might be a loss of SOD1 mutase activity, superoxide dismutase activity, turns out the mechanism is overwhelmingly a toxic gain of function through development of a misfolded protein. Where do we stand in the broader therapeutic landscape? You perhaps know that the FDA recently provided an accelerated approval for tofersen, which is an SOD1 antisense oligonucleotide developed by Ionis and Biogen. The idea of this is that it's an ASO. It recruits RNase H and leads to degradation of the SOD1 RNA, and this leads to no production of the misfolded protein. It is not allele specific and knocks down both wild type and the mutant form. What do these results look like? I think there's important lessons here as we think about developing therapies in the SOD1 space. This is the effect of this SOD1 ASO on clinical function, and this is looking at this outcome measure called the ALSFRS-R. That's the ALS Functional Rating Scale. It's a core functional outcome measure of disease severity in ALS. The primary outcome was measured at week 28, and you can see the group in red started on drug, and the group in blue started on placebo. Although there's a separation at 28 weeks, there is no clinically meaningful or statistically significant difference in the outcome between those two. When you look at the end of the open-label, not the end, but at week 52 of open-label drugs, so an early treatment versus a late treatment, as the placebo group switched over to active drug, you can now see a clinically meaningful difference, and a statistically meaningful difference between those two groups. Perhaps even more important than this is the impact on biomarkers. I'll show you first the impact on CSF levels of SOD1 protein, which we expect to knock down. You can see there's about a 30% reduction in the level of the SOD1 protein. This knockdown occurs over about 12 weeks and is sustained out at week 28 and out at week 52, and as patients go on to active drug from the placebo group, we see the same effect. Perhaps even more important and relevant to the regulatory decision is the impact of this ASO on this biomarker called neurofilament light, and I'll tell you more about this, but we see about a 60% reduction in neurofilament light levels. Importantly, that's in blood. This is plasma levels, and you can see once placebo patients go onto drug, the same thing happens. It's this reduction in neurofilament light that supported the accelerated approval by the FDA. The FDA viewed this reduction in neurofilament light as a candidate, or not as a candidate, as a surrogate biomarker reasonably likely to predict a clinical benefit. That was based on the preponderance of evidence that exists in the peer-reviewed literature about what we know about neurofilament light. What is NfL? Well, the neurofilaments, broadly, these are major structural components of nerve cells. When nerves degenerate in ALS and other neurodegenerative disorders, they're released into the spinal fluid and into the blood. They're light and heavy chains. There's also a medium chain. Perhaps most relevant is that these are very reliably measured. We have very robust technology and a variety of different assay platforms, to measure neurofilament, and this can be done, as I say, reliably, in blood. I want to just take a sidetrack for a moment and talk a little bit about biomarkers, because I think they're very relevant to therapy development in ALS broadly, and certainly in SOD1-ALS. When we talk about biomarkers, we need to think in terms of the FDA's language around thinking about the context of use for biomarkers. Many of these contexts of use are relevant to developing therapies for SOD1-ALS. I'll draw your attention first to the idea of a predictive biomarker. A predictive biomarker is one which tells you which patient is most likely to benefit from which treatment, and the genetic causes of ALS serve as those predictive markers. The example here is the mutation, the SOD1 gene, tells us who is likely to benefit from an SOD1 knockdown strategy. We lack this approach in non-genetic forms of ALS, but for the genetic forms, we have those predictive biomarkers in the genotype. There are response markers. These can be pharmacodynamic, they can also be surrogate endpoints. I mean, the examples I'll give you here are a biomarker that's elevated but stable, or a biomarker that's increasing over time as disease progresses. The FDA's view on this is that if you are given experimental therapy and you can lower the level of the biomarker or blunt that rise, that serves as a response biomarker. This is what we see with the tofersen data with neurofilament light. There are prognostic markers, and NfL has this role as well. Prognostic markers are those that we can measure at baseline or at randomization and are helpful in trial design, typically shortening study duration and reducing the number of patients needed in order to demonstrate a clinically and statistically meaningful benefit. These are markers that might be relevant to predicting survival or functional decline. Neurofilament light actually is a very powerful prognostic marker and was incorporated into the analyses that were done as part of the tofersen program. Lastly, I'll say a word about the role of neurofilament light as a risk or a susceptibility biomarker. The idea here is that this is a marker that can be measured in a population and which tells us something about the future risk of developing disease. What we know is that in SOD1 mutation carriers, if neurofilament levels are elevated, and these are pre-symptomatic individuals who've not yet developed ALS, if their neurofilament levels are elevated, they are much more likely to go on to develop ALS within a relatively short period of time, which gives us a paradigm for thinking about disease prevention. Let me just go back. What then, let me summarize, do we know about neurofilament light as a biomarker for therapy development in ALS broadly and in SOD1-ALS specifically? What I've schematized out here are the rises in neurofilament that we see over the course of disease. This in green is a slower progressing patient, in red is a faster progressing patient. We know that neurofilament levels rise pre-symptomatically as a marker of axonal degeneration. They continue to rise in early symptomatic disease and then plateau. Typically, by the time we see patients who are affected, they have a stable level of neurofilament that acts a little bit like a speedometer. It tells us how fast disease is progressing. That's why it has prognostic value, and because it's stable, it has value as a response marker. If we can knock it down, tells us that there's been a biological response. Let me just shift gear and tell you a little bit about how we might use this in a prevention paradigm, and we're doing this currently with tofersen. We are taking SOD1 mutation carriers in this trial called ATLAS. These are unaffected individuals. We are following them with their neurofilament light levels. When neurofilament levels go up, if they remain pre-symptomatic, we randomize them to drug or placebo, the primary outcome in the trial is the development of clinical ALS, at which point they go on to open label drug. If they develop disease without a rise in neurofilament, they go on to open label drug. What's relevant about this is when the FDA granted accelerated approval to Biogen, they identified this trial as hopefully providing confirmatory evidence of efficacy that will hopefully lead to full approval. What then is the unmet therapeutic need for SOD1-ALS, given that we now have an FDA-approved SOD1 ASO? Firstly, in the trial, and we don't yet know in the real world, but certainly in the trial, there was disease progression despite tofersen. There's also the potential for a greater therapeutic effect with more marked lowering of CSF SOD1. I'll remind you, in the tofersen program, that reduction is about 30%. We think there may be value in lowering it further, but not lowering it to nothing where there may be some potential harms. I think there's also value in developing a therapeutic paradigm that entails less frequent intrathecal dosing. The way tofersen is dosed is there are three loading doses, two weeks apart, and then monthly dosing, and that has to continue forever. If you're an affected individual and this works, or if you're a pre-symptomatic individual, that would require lifetime intrathecal dosing with a frequency of monthly. I think over time that's going to prove to be challenging. What are some of the lessons from the tofersen drug development program that I think are relevant to future trials? I think perhaps most importantly is the value of NfL as a response biomarker that's acceptable to the FDA. That's built upon the foundation of a robust scientific literature. I think there are things that we can learn about trial eligibility, and we can get into this in the Q&A if there's time. How we think about the mutational spectrum, the use, or I would say not, of the pre-slope of the ALSFRS-R, and thinking about disease duration with a premium on treating early. We should also incorporate NfL as a prognostic marker prospectively, either via stratification or via dynamic randomization, that'll make trials more efficient. Then we need to think about trial duration. I think one of the lessons from the tofersen program is that six months may be too short, pivotal studies should probably be longer. What then are the potential paths phase III for your compound? Well, I think we have to think about geographies where tofersen is not available or won't be available. We should think about head-to-head comparisons, either a non-inferiority or a superiority design for efficacy, and thinking about superiority with regard to safety and patient tolerability. I'll remind you of that monthly intrathecal dosing with tofersen. I think it's probably premature to phase III should be designed, but the full array of options, I think, is really critically dependent on the results of the phase I study, as well as longer term efficacy and safety data, which will emerge over the coming months and years as tofersen gets into the clinic. I will stop there. Thank you very much. Thank you, Michael. That was absolutely terrific. Good morning. I have the privilege today to share with you the data that the team at Arrowhead has been working on for the past couple years to develop our new CNS targeting program. I have to share also, I've been in the RNA therapeutic space for more than 20 years, and this is the most exciting thing in terms of impact to patients that I've ever done. There are more than 50 million people worldwide affected, living with neurodegenerative diseases. It's the leading cause of disability, and there's almost no therapies available. On the right side, we're listing some of the most prominent examples of these diseases. These include ALS, Alzheimer's, Parkinson's. Probably every single one of you know somebody that's been impacted by one of these diseases. They have different clinical symptoms and impact different regions of the brain, but they all share a common feature of being caused by abnormal protein aggregation, which results in toxicity to brain cells. Now, this has been a very difficult mechanism to drug using traditional modalities, but with RNAi, we can get right to the root cause and knock out the toxic protein. This is a really powerful tool to have, and it's coming at a time, which you just heard about, of really rapid progress in our understanding of the genetic cause of these diseases and the identification of biomarkers that are really enabling more effective clinical development, really increasing the probability of success. It's in that context that we developed the new CNS targeting TRiM platform. This is just outlining some of the key features. In terms of the design, it is a simplified lipid conjugate, and with this, we can achieve potent target RNA reduction throughout the brain and spinal cord and to all relevant cell types in preclinical models after intrathecal injection. Just as we've seen for the liver and lung TRiM platforms, we have a long duration of action, which can enable infrequent dosing, potentially half yearly. For safety, we can say that for our first program, we've now completed the GLP tox, and our NOAEL was the highest dose tested in both the rat and the monkey. You just heard about SOD1-ALS. ALS, of course, is a devastating progressive motor neuron disease that can be fatal within a few short years. SOD1 mutations are one of the most common genetic causes of ALS. Those mutations, again, result in abnormal aggregation of the protein, making it a good target for RNA therapeutics. You heard about the biomarkers that are available in this space to tell us that we've hit the target. SOD1 protein in the CSF is used as a surrogate for SOD1 protein reduction in the brain and spinal cord. We'll know right away that our platform is performing and hitting the target as expected. Of course, NfL is a very powerful marker, and as a reasonably likely surrogate to predict clinical benefit, offers a lot of opportunity for efficient clinical development. You know, as the accelerated approval of Tofersen a few months ago is a really exciting milestone. It's a huge advance for patients. There's definitely room for improvement. The limited efficacy with only 30% reduction of SOD1 in the CSF is correlated with a lack of... They failed to demonstrate clinical benefit in the pivotal trial. There's a need for better efficacy, and this monthly lumbar puncture is an enormous burden for patients, so a longer-acting therapy really has a potential to make a difference. We think ARO-SOD1 has the potential to achieve both of those things. Let me show you some of the data. First, we're looking here in transgenic rodent models. These are rats and mice that are expressing a mutant human SOD1, and they do, over time, develop ALS. On the left is the transgenic rat. We're looking at, simply at a dose response, at SOD1 RNA reduction after a single intrathecal dose, this is one month post-dose. You can see that we get, at the top dose, maximal efficacy of 95% reduction in SOD1 RNA. Very potent, deep knockdown. The ED50 or the amount the drug needed to knock down SOD1 by 50%, we calculated 33 µg, which is lower than what was reported in literature for tofersen. On the right is a similar experiment in the transgenic mouse, again, maximum 90% reduction in SOD1 RNA, and our ED50 of 13 µg is five times lower than what was reported in the literature for tofersen. We're getting potent knockdown in brain regions that matter, and if you look in the... We're looking at those biomarkers in the CSF that you've heard so much about now in the rat. On the left is SOD1 protein in CSF, and this is now three months after a single administration intrathecal. In this dose range, we're seeing 75%-90% reduction in SOD1 protein. On the right, of course, I've mentioned these animals develop disease, so neurofilament levels are elevated. At this time point, three months post-dose, we see neurofilament completely suppressed. As a marker of disease activity, this shows we're really suppressing disease development. You can see that more clearly in the transgenic mouse, where we've completed a survival study. Here we're looking at motor function measured by these behavioral tests, grip strength, and rotarod, and survival. Here, we've given a single administration to the mice at about nine weeks old, and we also made the tofersen ASO and put it in head-to-head. If you just focus on the left here, the black line is the control group, and we're looking at survival. What you see is that on average, these mice survive 155 days. The tofersen is the yellow line. It extends that by about a month, ARO-SOD1 treatment extends that by about four months. The lifespan of these mice went from five months to nine months. Pretty significant. You see very similar patterns with the grip strength and rotarod performance. Just shifted a little bit in time, about a month, preservation of function for about one month with tofersen, four months with ARO-SOD1. In the non-human primate, we've also looked at the activity of ARO-SOD1, and on the left panel, you can see the mRNA reduction throughout the brain, different brain regions in the monkey at one month after a 45 mg dose, and this is intrathecal lumbar puncture. If you just focus on the first six bars, those are the spinal cord and cortex. Those are the regions most relevant for ALS, and you can see 80%-95% reduction at the RNA level in those brain regions. Importantly, if you look across all of these brain regions, we are seeing really profound, 80% or more, reduction in many different regions relevant for those other diseases that were on that list that I first showed you. Cerebellum for ataxia, hippocampus for Alzheimer's, substantia nigra for Parkinson's, even the caudate and putamen. These are deep brain structures that are known to be difficult to reach. We're still able to see 50% reduction. This tells us that our TRiM platform is ready to be applied to many different indications. On the right is, we also looked at the, what cell types we're getting trigger the RNA delivered to, the siRNA delivered to. This is a section of a monkey cortex, and we're staining for the siRNA. This is a in situ hybridization method. The pink is the siRNA, and you can see that those large neurons are taking up plenty of pink siRNA. You probably can't see it from out there, but the yellow-stained astrocytes and the blue-stained microglia also have plenty of pink dots in there. This is important because all of these cells are known to contribute to the pathogenesis of SOD1-ALS and many of the other indications on that first slide. We've also looked at the dose dependence in the monkey. I'm a pharmacologist. I wanna know where we are on the dose-response curve. Again, here, we're just focused on the spinal cord and the cortex and looking in a dose range from 5 mg. If we lower the dose to 5 mg, we're still seeing really profound, deep knockdown in most of these brain regions, so this is very potent in the monkey. Finally, the duration of action. We've looked in the non-human primate at up to six months now, and on the left, we're looking actually at SOD1 protein, not RNA now. At one month, day 29 here, looking at the spinal cord and cortex, you see we get around 50% reduction in SOD1 protein. By three months, we're getting 80%-90% reduction of, at the protein level in all of these brain regions. This is actually, SOD1's well known to have a long half-life, so it was expected that it would take some time to reach the maximal knockdown level. Importantly, you can see that that knockdown is sustained out to six months. The SOD1 protein in the CSF, which again, is our translational biomarker that we'll be able to monitor in patients, is meant to reflect the protein knockdow n in the brain, and it does. You can see it follows a very similar time course. We get about the maximal reduction, two months or so post-dose. It's 60%- 70% reduction is sustained for six months. This compares very favorably with the tofersen published data showing required 175 mg administered to achieve 50% reduction. With this data in hand, we're now moving to our first clinical study. This is designed as a placebo-controlled, single ascending dose in symptomatic SOD1-ALS patients. The primary endpoint is safety. The secondary endpoints will include PK and PD or biomarkers that we've been discussing, the SOD1 in the CSF, the SOD1 protein for target engagement and neurofilament as a marker of response to treatment. We'll have also include some exploratory clinical endpoints, ALSFRS-R, and measures of motor function and lung function. Patients will be monitored for up to six months, potentially longer, if necessary, depending on the duration of action. Now that you've seen the data, we hope you're as excited as we are about what we can do with this platform. We think ARO-SOD1 could be a best-in-class therapy for SOD1-ALS, with better efficacy and longer duration of action, a better option for patients. As I mentioned, the GLP tox is complete, and we're now looking forward to a CTA submission in the next two months. We're also looking beyond ALS to the broader opportunity to bring disease-modifying therapies to neurodegenerative disease patients, and we are now moving forward a portfolio of programs, more is coming. Thank you. All right. Thank you, Christy. Can everybody hear me okay in the back there? Good. While we're very excited about the work that has gone into the intrathecal program, I just wanna highlight some of the additional platform expansions that we're making, including a program designed to deliver siRNA across the blood-brain barrier. This is an early-stage program. What we're showing here on the left, this is data in the mouse with IV administration. We're achieving upwards of 85% knockdown in various brain regions, including the cortex, the cerebellum, and the striatum, as well as the cord, with good duration of effect shown on the right. We've also taken this platform, which is a ligand-targeted platform, into the monkey. You can see here the knockdown that's being achieved in the cynos, upwards of 72% knockdown in the monkey. Importantly, this is being seen in the caudate, which is a deep brain region that is more challenging to reach with intrathecal routes of administration. We think that this platform could be administered either intravenously or with a subcutaneous injection. Here in the mouse, we're showing sub-Q versus IV, and you can see that with both routes of administration, we're getting between 80%-90% knockdown, maybe slightly favoring sub-Q administration, at least in the mice. We have a ligand-targeted platform. This is still in early development, but we see, at least in animals, an ability to deliver siRNA across the blood-brain barrier. We see that this route of administration, either IV or sub-Q, could have potential significant advantages over an intrathecal route if we're able to bring this into the clinic. We also see an ability to target the deep brain regions that are difficult historically to hit with an IT route of administration. This may be important for diseases, neurodegenerative diseases involving the deep brain, such as Huntington's. Another new platform that we've been working on is another ligand-targeted approach to deliver siRNA to adipose tissue. Adipose tissue collectively is the largest endocrine organ in the body, responsible for synthesis and secretion of numerous adipokines and cytokines that are involved in not only obesity and type two diabetes, but other conditions, including dyslipidemia, inflammatory disease, and even some malignancies. Here, we're showing data in the mice. This is targeting a gene that we can measure knockdown in the tissue, but also in the blood. On the left, we're looking at protein knockdown in the serum, so achieving upwards of 90% knockdown in the blood, with knockdown in the tissue at the tissue level of about 88%, so corresponding nicely to what we're seeing in the blood. We've taken this platform, targeting the same gene into non-human primates, and here, after a single 5 mg per kg dose, we're achieving maximal knockdown of 98% with duration out through week 31. We can maintain 85% knockdown or better for 31 weeks. The development of this platform is a little bit further ahead than the blood-brain barrier platform. We've taken this into non-GLP tox studies. At a high dose, at 120 mg per kg, we've seen no mortality in rats, no adverse changes in body weight or adverse changes in labs, including chemistry, hematology, or coagulation parameters, and no adverse findings on histopathology. One other area that we've been working on is the area of dimers. Two siRNA triggers covalently linked, but each targeting a different gene. What you can see here, the dimer is in green at the bottom, 6 mg per kg of a dimer, targeting two different genes, so target four and five, we're able to achieve deeper and better duration of knockdown when compared to the two same siRNA triggers administered separately. We see a lot of opportunity here for targeting the two different genes in the liver, also potentially two different genes in the lung. These are both liver targets that I'm showing here. I think we're going to take a break for Q&A. Okay, we got about ten minutes or so for Q&A, and there's a lot we covered, CNS, as well as the platform expansion. Brian and Jason are passing microphones around. We g ot some up here, Brian. Well, great. Thanks so much. Luca Issi, RBC Capital. Maybe a couple of questions here on the CNS. Maybe, Christy, could you just talk a little bit more about the chemistry here? I believe Alnylam is using C16 chemistry there to improve the lipophilicity, and I think they're using vinylphosphonate to improve potency and actually have tighter binding to the RISC complex. Wondering if you're using a similar chemistry here, and if you can comment more broadly on that. Maybe the second one, you know, I understand SOD1 sets a very favorable regulatory bar here, but just wondering the rationale behind going after this indications, given the relatively small populations in the United States. Thanks so much. Is this working? Yeah. On the chemistry part, I think we are also a lipid conjugate, but we do have different design features compared to what Alnylam has. I think we're similar enough that we think their recent clinical data should read through to us, and we're really excited to see that. The other part you want to say? Well, I think SOD1 is how we've developed the platform, and so I think we've learned a lot about what we need to do, and it's really just. It's a launching point for us. Yeah, I would agree with that, and I'll add just on the chemistry front, we do have our own, you know, a similar chemistry that facilitates RISC loading. It's not the vinyl phosphonate, but as Christy said, I think we should be, you know, similar in terms of potency. Then in terms of why SOD1, I mean, we have lots of targets that we're looking at. SOD1 was the first to find a sequence, and it also has a lot of advantages in terms of a measurable biomarker, a well-spelled out clinical and regulatory pathway. And we think there's room for improvement still over tofersen in terms of depth of knockdown and duration of effect. While there, the market size and the population in the U.S. may be small, there's still, I think, a lot of ways that we can improve upon what else is out there. Mani Foroohar, SVB Securities. We'll start on the adipose side. It looks like you're measuring a serum biomarker, which I presume is an adipokine or something else involved in signaling. To what extent does that read across to the intracellular knockdown and efficacy of risk loading inside the adipocyte? There's a lot of steps that up and down regulate signaling from what I presume is ghrelin, leptin, something like that. How translatable is that serum number to what's actually going on in cells? When can we expect to see something that looks more like an intracellular metric or some more direct m easure of knockdown on a single-cell basis? Sure. Yeah, I don't know that I can give you guidance on when we would show single-cell knockdown, and maybe Erik or Tal can cover that if we have it. The first slide that I showed was the knockdown in the blood, and then also the knockdown at the tissue level in the protein. That might get you closer to what you're interested in. We have the similar data in the monkey, and we haven't disclosed what the target is as of yet. I guess the other question is, to what extent should we think about the targeting to different types of fat tissue? Obviously, when you talk about adipocytes or fat tissue, it's. You go to a mitochondria meeting, there's 50 different types of fat tissue they talk about. How should we think about tuning for different types of fat tissue, or how should we think of this almost exclusively as subcutaneous fat targeting? How should we think about the nuances of where you're actually getting? Sure. Yeah. This platform should be able to target, all, you know, all types of fat, both the subcutaneous and visceral fat. In fact, the samples that we looked at in the rodent, those were, visceral samples. That's- I hope that's what you're asking. How do you guys think about target selection then for that delivery mechanism in terms of where... and what kind of indications you'd be chasing and where that fits into your broader pipeline? Sure. Yeah. We have actually a fair number of targets that we're looking at now. We're not ready to disclose those yet, but suffice it to say that I think the targets are in some of those disease areas that I had highlighted, including metabolic disease, inflammatory disease, and so on. Great. I'll pass the mic from back. Here you go. Hi, this is Faisal Khurshid from Jefferies. Thank you for taking my question. Did you compare the neurofilament light chain reduction and biodistribution for the mock tofersen related to the siRNA? What sort of difference are you seeing there to explain the survival b enefit? I'm not sure I heard the question completely. Could you repeat that question? Like, did you compare the neurofilament light chain reduction and biodistribution for the mock tofersen related to the siRNA SOD1 that you used? Oh, I see. In the rodent models, you're talking about? Right. why do you see the survival benefit? That's the- We have that data. I think the neurofilament will rebound as the activity of the compound wanes. That will map very closely with the graphs that I showed, I think, is the answer. Yeah. Great. Thank you very much. Edward Tenthoff, Piper Sandler. When it comes to CNS and obviously advancing towards the clinic with SOD1-ALS, is the plan here to achieve proof of concept initially and then look into other disease areas, or will you already be starting to prioritize other CNS trends? As it comes to sort of taking these further, is this an area where you would envision partnering either on a product-by-product basis or even doing a large, maybe CMS-type deal? Thanks. Chris. Sure. The first, the first question first, you know, are we waiting to see proof of concept in the clinic before we move forward on other targets? The answer is no. You'll hear about more targets later this year. We have a pretty good staple of targets, I think. With respect to partnering, you know, I sort of view CNS in a similar way as I view pulmonary. It's a target-rich environment. You know, as we've said publicly, in the past about pulmonary, we don't see two or three drugs, we see nine or 10 or 11 drugs. Same thing with CNS. I think there is room there for some partnering, as well as for retaining and holding owned assets. It's hard for me to imagine us not commercializing, you know, some staple of CNS drugs. We will certainly hold on to some. Again, there, you know, we are so good at bringing new drugs into the clinic that, we've got, you know, plenty of ammunition to also bring in the right partners for some of those. Hi. Thanks so much. Ellie Merle, UBS. Can you comment a little bit more on the safety, particularly anything in terms of, you know, chronic tox preclinically of siRNA and any theoretical concerns that you're thinking about for siRNA versus ASOs? If you can comment, maybe any perspective on APP and some of the recent updates in the space there. Thanks. I'm guessing that that question is specific to the CNS platform. You know, I think all we can say is based on what the data we have in hands that comes from the GLP tox study, where, as Christy mentioned, the top dose was the NOAEL. We feel like we have a good room to work in terms of margin of safety in the phase I study. My understanding is the problem that Alnylam ran into with APP may have been related to frequency of dose in their GLP chronic tox study. I think that, you know, it's, there are pluses and minuses to being first, and one of the minuses is that you get to, you know, figure out things like that the hard way. Suffice it to say that we will be sure to have sufficient duration as allowed by our pharmacodynamic effect in our tox studies. I think we had one more up here. Madhu? Last question for this session. Yeah, maybe following on the adipose program, what is your line of sight for kind of developing adipose targets? Like, I mean, do you think that there's in the time frame of, say, the blood-brain barrier scene? I think, do you have any rough gauge of where you are in terms of giving the unpredictability of RNAi preclinical drug development? Do you think you have a line of sight as when you could actually get an adipose-directed drug into the clinic? Yeah, I can say that we have a target that we've identified, and we're in the process of screening triggers against that target. I can't guide on exactly when those would make it into the clinic, but we do have a program, I guess, is what's important. All right. Thank you. I will turn it over to Erik, who's gonna talk about pulmonary. Thank you. Thanks, Vince. Just wanted to take the opportunity to reintroduce the latest generation of our pulmonary delivery platform that we introduced in this meeting o year ago, as well as our clinical-stage pulmonary programs. The latest generation of our pulmonary delivery platform utilizes the same algorithmic approach to siRNA design, but it employs enhanced modification chemistry to improve the depth and duration of knockdown in vivo. It utilizes the same integrin αvβ6 targeting moiety to drive epithelial cell uptake in the lung. What this translates to is that via inhalation, we see increased potency of our siRNAs and target knockdown. This is related to preferential delivery and uptake of those siRNAs by epithelial cell types in the lung versus non-targeted cell types, such as pulmonary macrophage. This is driven by transient internalization of the delivery receptor. We've looked for any evidence of potential downstream receptor pharmacology associated with receptor internalization, such as elements of TGF‑β axis like SMAD protein phosphorylation. We've seen no evidence of that, so that's a transient event. Also related to the platform, we have confidence that after inhalation, we see good delivery through airway mucus. We know the physicochemical properties of our pulmonary delivery platform is compatible with transit through the mucus. The conjugates are a very small size in the order of 3 nm-10 nm, so an order of one magnitude or more smaller than the pore size of the mucus itself. They harbor a net negative charge, which is favorable with respect to potential electrostatic interactions with airway mucus. These conjugates are soluble in aqueous solution. You know, as we've shown in the past, we have multiple lines of evidence for efficient delivery through the airway mucus, both in vitro, in cultures with mucin on top, as well as various in vivo models of mucus hypersecretion. Moving on to targets. Our first target to speak to today is the receptor for advanced glycation end products or RAGE. This is a fascinating target for inflammatory lung disease. At a very high level, this is the pro-inflammatory pattern recognition receptor, highly abundant in lower airways in type one alveolar epithelial cells, but expressed at very low quantities throughout the body and other organs. It is activated by a very broad milieu of different pro-inflammatory ligands. These are sugar-modified proteins and lipids, otherwise known as advanced glycation end products, a variety of immune cell alarmins, in particular HMGB1. The signaling through this receptor culminates in canonical NF-κB pathway activation and results in secretion from the airway epithelium, a variety of pro-inflammatory second messenger cytokines, mucin secretion, and so forth. As we'll hear from Dr. Salathe momentarily, this receptor is very important to amplify and sustain chronic inflammation through other inflammatory pathways. The knockout phenotype of the mice have been well studied, and they show a striking resistance to a variety of allergic and inflammatory airway stimuli. Despite this, you know, very promising biological validation, it's proven very difficult to drug with small molecules. The structure of the receptor is highly related to immunoglobulins, so there are very many potential interfaces for interacting ligands, which of course makes traditional small molecule antagonist design almost impossible. We also like this target because it is processed or it's cleaved in the lung, where it sheds a soluble version of the receptor, or sRAGE, into the lavage fluid and into circulation, and that can be measured as a surrogate for target engagement. What we're showing you here is a summary of some data that was presented at ATS last year. This is rats that received a single inhaled aerosol dose of a RAGE targeting conjugate at a half mg per kg deposited dose. In blue, we're following the whole lung gene expression of RAGE. As you can see, within three days of dosing, whole lung RAGE knockdown is greater than 90%, and it remains in this range for multiple months post-dose. Serum sRAGE in the blood, detected as a target engagement marker, takes longer to clear as the burden of receptor in the lung is processed and cleaved and cleared, and it takes about a month lag to see the full knockdown in serum sRAGE. If you look at the actual receptor itself at the protein level by immunohistochemistry at day 36, you can clearly see here, complete depletion of protein. Moving from there, establishing good knockdown in the rat, we move to rat models of allergic asthma, seeking to phenocopy elements of a knockout mouse here. We use sensitized rats that are exposed to a fungal allergen, Alternaria alternata, to provoke lung inflammation in those animals. We can study that lung inflammation in a number of different ways, but simply we're showing here bronchial or alveolar lavage collections. In response to fungal allergen challenge, these sensitized rats have profound pulmonary inflammation, evidenced by an immune cell infiltration, so eosinophils, neutrophils. We see elevations in a wide range of cytokines, such as IL-13. Similar to what was seen in the knockout mice, suppression of RAGE expression by RAGE silencing effectively reduces all of these inflammatory markers, both eosinophils and notably neutrophils. Moving to cynomolgus monkeys in non-human primates, here we gave a single inhaled aerosol dose of our ARO-RAGE clinical candidate, and we see very good deposition and activity of the drug across all anatomical regions of the lung, resulting in 90% or more silencing with a single inhaled dose. Some new data here that we wanted to share. This is a dose response in cynomolgus monkeys via inhalation. These are single inhaled doses with animal sacrifice at day 29 post-dose. We're looking at doses ranging from 0.13 to 0.47 deposited dose. Looking first at lung expression of the target itself, this is membrane-bound, full-length receptor RAGE, and we see a good dose-dependent reductions, with the highest deposited dose resulting in 88% knockdown at the protein level. Looking at our surrogate biomarkers of target engagement, in this case, BAL sRAGE, we see BAL sRAGE pretty closely match with what's happening in terms of full-length receptor knockdown in the lung. However, in the cynos, serum sRAGE appears to underrepresent the depth of lung knockdown of full-length receptor in these animals. We, we think, at least in the cyno monkey, compared to the rat, that there may be some extra pulmonary source s of sRAGE that will drive a higher baseline. Moving on from RAGE, to MUC5AC targeting for various muco-obstructive lung diseases. To briefly introduce the mucins, in the lung, there are two major genes that encode gel-forming mucins that are expressed to form the mucin gel in the airway that rides on the airway surface liquid. These are very large, heavily glycosylated proteins, and the two genes are MUC5B, which is constitutively expressed. It's the major component of airway mucin, comprised of 90% or more-... and it is required for mucociliary clearance. Knockout of this is lethal, and our siRNAs are highly selective for MUC5AC and do not silence MUC5B. MUC5AC is a minor component at baseline and at the mRNA and protein level, comprising 10% or less. You can see here in airway epithelial goblet cells, there's very little accumulated protein, but under settings of inflammation or allergen challenge, there is a very profound upregulation of this mucin. It accumulates in secretory granules in the goblet cells. You know, what does that mean for patients? What that means for severe asthma and a variety of muco-obstructive lung diseases, there's a wonderful literature in this space for a very challenging target, is that if we look at airways in healthy individuals, this is a cross-section cartoon. The predominant component of healthy airway mucin is MUC5B, a very minor component with MUC5AC. In settings of chronic inflammation, such as asthma, there's a much larger MUC5AC component, and the biophysical characteristics of MUC5AC when it's combined with MUC5B, lead to a much stickier and harder to clear, mucus, that results in impaired mucociliary transport and sometimes even plugging in fatal asthma. The genetic basis of this target was first uncovered, a number of years ago in 2015 by Burton Dickey's group, who made the first knockouts here. A bit of a surprising finding here was that in these animals, that Whoops! Can I go back? Produced no airway MUC5AC, is that, in these animals, these animals were resistant to airway hyperresponsiveness. If they were given an allergic challenge and then provoked with bronchoconstriction, they found they were completely protected from airway hyperresponsiveness, showing that it was a combination of this sticky mucin in airways, combined with bronchoconstriction that was driving airway dysfunction. Moving to our mouse models of allergic asthma, we're able to study this in the same way. We stimulate mice with house dust mite allergens or IL-13. I just want to point out that in normal mice at the mRNA level or in airway immunohistochemistry, there's very, very little MUC5AC expressed. This can be driven very high with an allergic stimulus, hundreds of fold increase in MUC5AC expression. You can clearly see the burden of this in airway goblet cells. What we find with our siRNAs is that we're consistently able to get in the 70%-90% range of silencing of MUC5AC at the mRNA and protein level, and we've translated this through to cynos. Really, what's important is the consequence of MUC5AC silencing on airway function, and we've studied this in a large animal model of allergic asthma. These are sheep that are sensitized to Ascaris nematode antigen, and they can be provoked into an allergic asthma attack by giving them this inhaled allergen. What that looks like over time is a very stereotypical set of physiological responses that are seen in humans having an allergic asthma attack. They have an immediate sort of late-phase response that occurs four to eight hours post-challenge, and then a lingering airway hyperresponsiveness that's very difficult to treat. In sheep, what we're looking at is airway resistance or lung resistance in the hours post inhalation of this challenge. They start from having very good lung mechanics to four to eight hours post-challenge, airway resistance increases by 100%. In this late-phase response, we see a dependency of this response to MUC5AC, because we see a dose-dependent reduction in late-phase response. Critically, the really challenging piece to treat is the lingering airway hyperresponsiveness. Within 24 hours, these sheeps tend to their airway mechanics return to baseline, but they're still highly sensitive to bronchoconstriction. If we give them a bronchoconstrictor, have them inhale carbachol, we can measure the number of breaths those animals need to take in order to get a 400% increase in airway resistance. This is modeling an asthma attack. In these sensitized sheep that have not received ARO-MUC5AC, it takes them about 20 breaths of carbachol to get that 400% increase. If they've had that ascaris challenge or that allergen challenge, 24 hours later, without treatment, it only takes about half the number of breaths to get that 400% increase in airway resistance. If those animals had been treated with ARO-MUC5AC, they look identical to their non-challenged control measurement. This really highlights the important role of MUC5AC in airway hyperresponsiveness. Dr. Salathe will speak in a bit greater detail here on MUC5AC. We expect treatments for MUC5AC to be broadly applicable to a range of muco-obstructive lung diseases. We're just highlighting here clinical data from patients that have provided induced sputum samples and looking at total mucin concentration in that sputum. In healthy people, mucin concentration is rather low, but it's almost exclusively MUC5B, as I've mentioned before. We look at patients from asthma and COPD all the way up to patients with cystic fibrosis or primary ciliary dyskinesia. There's more and more mucin, but critically, the major increase, the major contributor to this increase in this sticky, hard-to-clear mucus is MUC5AC. Finally, transitioning to our third clinical program, our newest program. This is a program targeting matrix metalloproteinase- 7 for idiopathic pulmonary fibrosis. This is our first entry into interstitial lung disease. MMP-7 is a protease. It's secreted by injured epithelia. It's one of a very large family of proteases with very diverse gene functions. Notably, although it's expressed at rather low levels in the lung, in IPF, it is one of the most upregulated genes in lungs of those patients. It's in fact been used regularly as a validated IPF biomarker. It predicts disease severity and progression. It also contributes multiple roles to IPF pathogenesis, promoting inflammation, aberrant epithelial cell repair, and fibrosis. The knockout mice are robustly protected from standard models of bleomycin injury, that piece comes together there. Despite these understandings for a number of years, matrix metalloproteases have been really difficult challenges for traditional drug discovery, simply because to achieve these effects, you need to have highly selective inhibitors against specific members of this family, and these all share essentially the same catalytic domain. That's an almost insurmountable challenge for small molecules. I'm just gonna walk you through just very high-level highlights of data that was presented at our ERS meetings last year. You can find these results on our website in much greater detail. Just simply touching on our work to validate proof of concept in rats. Yeah, we use the rat bleomycin injury model. With this insult, there's a profound pulmonary inflammation followed by fibrosis. That can be read out, even, you know, histochemically, you can see accumulation of lung fibrosis. This can be scored with a standard Ashcroft pulmonary fibrosis scoring system. What we find in rats, that doses of MMP-7 silencing siRNAs that achieve 50% or greater silencing were highly effective at blocking fibrosis. You can see the fibrosis score of these MMP-7 silenced animals mostly shifting into the moderate to mild, and this was accompanied by significant reductions in airway and lung inflammation, improved pulmonary function, and significantly reduced mortality. From there, we transitioned with our ARO-MMP7 clinical candidate into non-human primates in dose-response studies, given a single inhaled aerosol dose ranging from 0.24 to 1.7 mg per kg. We see a robust, anatomically well-distributed knockdown of MMP-7 throughout the lung, and have confirmed the same level of knockdown in cultured human lung slices as well. I think with that as prelude, I'll turn it over to James to walk us through some of the new clinical data. Thank you. Thank you, Erik. Just give an update on the various clinical programs, and we'll start with MUC5AC. Briefly, just an update on the study design. This, like the other programs, uses a single and a multiple escalating design, starting in the healthy volunteers and then in the asthma patients. In the healthies, we do collect sputum samples throughout the study in both the SAD and the MAD part of the study, and then the healthy volunteers in the multi-dose cohorts undergo bronchoscopy pre-dose and then post-dose. The healthies are fully enrolled, and we've moved on to the asthma patient cohorts, where we are enrolling patients with moderate to severe asthma, and these patients are currently enrolling. Similarly, in terms of dosing, they get dosed on days one, 15, and 29, and then we measure sputum after the third dose. No broncs in the patient cohorts. Key endpoints for the study, safety endpoints include respiratory AEs, changes in lung function. We're able to measure in the healthy volunteers, changes in inflammatory cell counts on BALF, then we can also look at any changes in chest X-ray. In terms of biomarkers for target engagement, we can measure MUC5AC protein in the sputum and also in the airway swabs. Importantly, as Erik has already highlighted, it's really in the patients, the asthma patients, that MUC5AC is upregulated. In the healthy volunteers, the mucin in the sputum is mostly MUC5B, very low levels of MUC5AC expression in the healthies. Safety so far has looked good, with no serious or severe AEs, no dropouts from the study, no AEs due to adverse changes in lung function, and no adverse changes in BALF cell count, so no indications of inflammation or inflammatory cell infiltrates on the BALF. The chest X-rays have all been read as normal, pre-dose and post-dose, and there's been no pattern of adverse laboratory changes. Next steps for this study. So far, we've seen a favorable safety profile, and we're in the process of evaluating the MUC5AC samples in both the healthy volunteers and the muco-obstructed patients. We continue to enroll the asthma patient cohorts, and we plan to enroll two additional cohorts that Javier will give some details on in a few slides here. Specifically, cohorts of COPD that will run in parallel to the asthma patient cohorts. We've decided to do this because we view this as not only a large patient population, but one where MUC5AC expression is significantly upregulated and also an area where there have not been a lot of new advancements in therapies. The treatments today for COPD are similar to what was used, you know, a couple of decades ago. We view a lot of room to improve therapeutic options in COPD. We're also investigating the possibility of adding some additional studies using novel biomarkers, including changes in airflow based on MRI in both the asthma and the COPD cohorts. Moving forward to MMP7. This study is still in early days. We have enrolled just the first two cohorts in the healthy volunteers, a similar study design with single and multiple escalating dose cohorts in the volunteers. Then at, after the volunteers are all enrolled, we will enroll IPF patients at doses that are still to be determined. Just a point on the biomarkers that we can measure for MMP7. Similar to the situation with MUC5AC, we can measure MMP7 in the blood and also in the BALF in healthy volunteers, but it's really in the patients, the IPF patients, that have this ongoing inflammatory and fibrotic process that MMP7 is upregulated. So we really look forward. We haven't seen any data, the data from the healthy volunteers in this study yet, but we look forward to the patient cohorts being the most informative in terms of pharmacodynamic effect. On to RAGE. This is the study that is the most advanced, similar study design with single and multiple escalating dose cohorts starting in the healthies. The healthy volunteer cohorts here are almost fully enrolled. I think we have a few more at this last cohort down here, B5. That's the highest dose. Highest multi-dose cohort is nearly fully enrolled. We've started enrollment in the asthma patient cohorts and have only this first cohort, 44 mg, is fully enrolled. The endpoints are similar in terms of safety, respiratory AEs, lung function, BALF cell count, and chest X-rays. However, with the RAGE program, we do have a fairly versatile biomarker, that being sRAGE or soluble RAGE, which we can measure both in the BALF but also in the blood. As a reminder, while we can measure sRAGE, what is most important is actually mRAGE, which is the membrane-bound RAGE component. This is what binds. It sits on the surface of the epithelial cell and binds to the PAMPs and the DAMPs, the pathogen-associated molecular patterns and damage-associated molecular patterns, and trigger the downstream inflammatory cascade in both the T2-high asthmatic patients and as well as the non-T2 asthmatic patients, also is likely involved in COPD. What we're showing here on the right, this is data from a rat study, single-dose rat study, that demonstrates the relationship of reduction or knockdown in RAGE at the mRNA level with the BALF, the serum, and the membrane-bound RAGE. I think you can appreciate that we are achieving great mRNA knockdown, but more importantly, that corresponds to knockdown in sRAGE, corresponds temporally as well as in magnitude of knockdown, and that corresponds to serum sRAGE and membrane-bound RAGE. The point of this all being that we think measuring sRAGE in the BALF and in the serum is a good proxy for what is going on at the membrane level. These are the data. This is new single-dose data. You can see on the left, after a single dose, the top dose level, 184 mg, we're achieving knockdown of 76%. That's mean knockdown after a single dose, so that's the red line at the bottom. We only have data out through day 29 so far, on the right, these are the individual participants in the study. In terms of the individuals, we're seeing a max knockdown of 91% after a single dose, again, at day 29. After two doses, serum sRAGE, a mean maximal knockdown of 80% on the left, and then a maximal knockdown of 90% seen here on the right. Again, the individuals on the right. Importantly, we're seeing good duration of activity. After two doses, after the second dose, we're getting duration that we think would be supportive of two-month dose administration, good duration, and we still have not seen the 184 mg data yet, and we'll share those data once they're available. The knockdown here is all with the 92 mg, not quite at the top dose level yet for the multi-dose cohorts. One of the questions we get asked is, "Can you knock down the target in the inflamed lung or the muco-obstructive lung?" We don't have a lot of data yet from the patient cohorts. This is really all we have so far. This is the lowest dose enrolled in the patient cohorts at 44 mg. Other than this kind of hyper-responder here in the healthy volunteers that are in blue, I think the patient knockdown data for sRAGE generally overlaps well with what we're seeing in the healthy volunteers. So far, I think the answer to that question is yes, it looks like we can knock down the target in the patient lung. Finally, the last slide here, this is the BALF knockdown. Again, healthy volunteers after a single dose. On the left, mean knockdown of 90%. This is from the top dose level, 184 mg, maximal knockdown on the right of 95% in BALF sRAGE. The safety profile so far has been favorable, with no serious or severe AEs or discontinuations. Like with the other programs, no AEs due to changes in lung function and no adverse changes in BALF cell count or chest X-ray, or adverse changes in safety labs. In summary, ARO-RAGE has achieved deep and durable reductions in both serum and BALF sRAGE in a healthy volunteer population, with similar silencing seen in the asthma patients. We believe this is the first compelling clinical evidence of gene target silencing in the lung using siRNA. The safety profile to date has been favorable, we look forward to presenting the full data in the healthy volunteers at an upcoming medical meeting. Like with the MUC5AC program, we're also adding a couple cohorts to this study. Specifically, we'll be adding cohorts enrolling asthma patients with a high baseline FeNO or high fractional exhaled nitric oxide. FeNO is largely a type two high measure. It's driven by IL-13, this should help us better understand the anti-inflammatory effect of ARO-RAGE in asthma patients that have a baseline high FeNO. Now I'll turn things over to Professor Matthias Salathe, who will help put some of these results into clinical context. Right. Good morning. I'm gonna talk about the targets and how they are relevant in different lung diseases. I think I need to figure out... What I'm gonna look at is both the RAGE and MUC5AC, and how I see them to be important in these different lung diseases that we already talked about. These are my disclosures. Let's start with asthma. I think this slide basically shows you the big two targets that we want to go at. Here is the airway in a normal human being. Here is an asthmatic airway. You see inflammation and narrowing of the airway lumen, but also mucus in the middle of the lumen, which makes it obviously much smaller. This is just depicted in a schematic for the same. How can we address that? First of all, asthma is a complex disease, right? This is not just asthma is not asthma, is not asthma. You see here that there is T2- high asthma and T2- low asthma. While we have reasonable treatments, and I say reasonable because they can always be improved, in T2- high asthma, there is almost zero treatment in T2- low asthma, and there is a huge need for that, at least for people who have related T2- low asthma. This is a significant. If you think about here, obesity-associated asthma, this is a growing need, in the U.S. population for sure. Here is what is available today beyond the regular treatment of inhaled steroids, and bronchodilators. You see the biologics. On top here is tezepelumab, which is basically the highest level of interfering with the inflammatory cascade that goes down here, and there is a bunch of other biologics on the market. When you look at decision trees to make treatment choices for these patients, it becomes actually very, very difficult to make these decisions, who is going on what treatment. The idea here is really what is on top of this inflammatory cascade, and if we can interfere with the top of that inflammatory cascade, then will we be better off than making these decisions down here? Like I said, this is mostly for T2- high, not T2-low asthma, where really almost nothing exists. Here you see an attempt of looking what happens to patients with tezepelumab in T2-high and T2-low asthma. Really what we should look at is these two panels diagonally. Here you see exacerbation risks of T2-high with blood eosinophils at over 300 and FeNO at over 25, that they have a significant reduction in exacerbation with this biologic. On the other hand, if you do not have this, if you're T2-low, your exacerbation decline with the treatment is much, much, much lower. There's huge room for improvement, especially in these group of patients, and these are sort of other intermediate patients in there. The top of that cascade is really RAGE, and I'm not gonna reintroduce RAGE now, but Erik did a great job at that. You can see it's really stimulated by a lot of different inflammatory stimuli, allergens, smoking, pollution, other these DAMPs and PAMPs that James mentioned as well. Even, you know, they really originated from advanced glycation end products, and that was recognized in diabetes. You know, sugar obviously is an issue there as well. RAGE, however, is not necessarily expressed very highly in normal, quote, "normal people." We can have a whole discussion about what normal means now. If you see biopsies here from the airway in people without asthma, there is not that much RAGE expressed, but it goes significantly up the more severe the patient's asthma becomes. That is true also in mouse models that are with allergy, treated TDI, and there is an increase in RAGE expression that can be at least partially inhibited with a RAGE antagonist. This is a small molecule, and we all know this is not a great treatment, at least so far in the small molecule space. RAGE is necessary for T2 inflammation. You see here, house dust mites, challenged mice with increases in cytokines. I have a hard time to read it from here. When you look at RAGE knockout, there is a significant decrease, obviously, in these open bars between the control mice treated with house dust mice and house dust mites and the RAGE knockout. RAGE sits really on top of this inflammatory cascade, and if we can block that signaling initiation, then we should block a lot of the downstream mechanisms. Importantly, RAGE is also needed for sustained inflammation. If you initiate an inflammatory cascade, that can be maintained, and the maintenance comes from RAGE expression that drives this continuous inflammation even after one stimulus. In RAGE knockout mice, this is completely blunted. You can get an initial response, but there will be no sustenance of any inflammation. What's also important is in mice models of T low inflammation, this is an Alternaria alternata model. There's a lot of neutrophil inflammation here in these mice, so it's not the eosinophilic inflammation, so it's a T2-low inflammation. You can see in orange, I don't know why they chose these colors, so it's okay. You see that there is a significant blunting, again, even of the T2-low inflammation in this mouse model with RAGE knockout. What seems to be important in this area is the inflammasome inhibition. Overall, from these data, at least in these animal models, it seems fairly reasonable to target RAGE as the top of this inflammatory cascade that is not only initiating but also maintaining the inflammation in the airway, and seems to work both in T- high and T- low inflammatory responses. This is not only in asthma. We know that COPD has also neutrophilic response, and you see that the neutrophils here, that RAGE is expressed also at higher levels in patients that are smoke exposed or have COPD. There is also a neutrophil relation to this inflammation, this goes now beyond asthma. Here, there is a mouse model with also smoke exposure, with a decrease in the neutrophils, with RAGE knockout, and a clear decrease in cytokines. This may be a model also for using this in COPD. There is a subgroup of patients with COPD and high type 2 inflammation. This makes about, you know, about 15% of the COPD population has that. There is at least one study that was just published in the New England Journal of Medicine, where there is actually a decrease, but a small decrease in exacerbations in these COPD patients with a biologic, in this case, dupilumab. This is a small decrease, but the principle there is clear that if you can target RAGE in COPD, you may actually have a much better effect, and it's not only in this small subgroup of patients, it might also be in the other patients that don't have a T 2- high inflammation in the airway. RAGE is not only in COPD asthma, here is cystic fibrosis. RAGE is increased in cystic fibrosis in general, and it's even worse in cystic fibrosis patients with diabetes. As you know, CF patients live now much longer with modulator therapies, but that means also they have more complications as they approach adult age. Currently, it's about 40%-50% of all CF patients have diabetes, and we expect that with aging of that population, there will be even more. There is a correlation also with blood glucose and RAGE expression, and here you see despite modulator therapy, patients who have diabetes have actually a still much more accelerated lung function decline than people on modulators with CF who do not have diabetes. There is an additional opportunity in this space. Now, I like this slide because it shows you mucus plugs, extracted from a lung, of an unfortunate patient who died from an acute asthma attack. You can all imagine that these mucus plugs are obviously not a good thing to have in your airways because you cannot breathe. As Erik already pointed out, these are all related to MUC5AC. Mostly related to MUC5AC. What's interesting is, why in the world do we have MUC5AC upregulated in there? From an evolution point of view, it is likely, even though Erik used Ascaris to challenge sheep, right? It was the Ascaris worm that came into the lung to be trapped by mucus plugs and not actually be swallowed again to have the infection with Ascaris. Today, this is obviously no longer needed, and we have now problems with this mucus plugging. Mucus plugging is a huge issue. This is true in COPD. You see MUC5B is not really that much changed, but MUC5AC is go up, and it is related to the severity of the disease as well. I come back to that because this is also related to actually how many mucus plugs, not only asthmatic patients have, but actually COPD patients have. Now there are a lot of studies that look at mucus plugs in the airway of COPD patients, and the higher the severity of the disease, the higher the number of mucus plugs. If you go backwards, there are some notions, at least from experts in the field, that up to 50% of the lung function loss in COPD may actually be to mucus plugging in COPD. If that turns out to be true, there is obviously a huge target to prevent further deterioration in COPD if you can prevent mucus plugging. Asthma has that as well. This is a little bit misleading because this is actually MUC5B over MUC5AC, so it goes down because it's getting worse with MUC5AC. I don't know why Mara plotted it like this, but this is published, so it's the opposite of what you see here in cystic fibrosis, where it also goes up because the ratio is MUC5AC to MUC5B. In all of these diseases, and then in non-CF bronchiectasis, which is a very heterogeneous group of diseases, there is obviously also a MUC5AC problem. Here is mucus obstructive disease in COPD, and I know this is a bit complicated, and I'll try to quickly go through this. On the left is the first time point of CT, where people were looked at with COPD who have mucus plugs in the airways. There's low mucus plugging or no mucus plugging, there is medium, there is high mucus plugging. This is one year later. What's interesting about this is that most people who are highly plugged stay highly plugged. People who are not plugged, they don't really develop plugs. There is a target group of people. They're very consistent with continuous plugging at the same location. In asthma, this is the same. You can look that up as well. What you also see is the severity categories are going up with the GOLD stage of COPD. The more severe, the more mucus plugging you have. The worse is your lung function. This is true mostly for COPD, but you see even some smokers with preserved lung function have the same problem. Again, it goes up, and the MUC5AC to MUC5B ratio is also somewhat related to severity. Again, even smoking at that risk has a target for this, where you really want to prevent mucus plugging. MUC5AC, when you look at mucus, I'm sorry, airway hyperresponsiveness, you see also that that contributes to viral exacerbations in COPD. Here are mouse data with MUC5AC knockouts, and you see there viral Sendai virus challenges of these mice has a much attenuated response to the Sendai virus, which is important. Also in humans, obviously, you cannot really challenge them with virus. I mean, you can, but that's usually not done. These are patients that are having exacerbations due to viruses. You see in their sputum MUC5AC is elevated as well. It is also an opportunity to look at exacerbations and potentially prevent exacerbations. Maybe we should think about airway diseases in a different way. You know, we think about airway diseases now more like a mucus obstructive disease and an inflammatory disease, and how these quadrants can be filled in with high mucus and high inflammation. You can see that these targets obviously are very good to go after because you can basically treat any of these four targets in there. In summary, I don't want to really read this throughout here, but I think there is a good reason to go after RAGE in multiple airway diseases, not only asthma, but also in T2-low and T2-high airway disease. This goes to COPD and cystic fibrosis and potentially other diseases as well. MUC5AC is really the mechanism of how mucus plugging and mucus obstructive disease is being seen in asthma, COPD, and other diseases as well. Going after that target will have a lot of beneficial effect if we successfully can silence that target in the lung. Again, that has no, at least from our animal data, negative effects, because for usual host defense, innate host defense, you need MUC5B, not MUC5AC. All right. With that, I thank you, and I'm giving it over to Javier. Hi, everyone. Thank you, Matthias. Well, what a section this, Erik told us a lot about the platform and the targets and the biology and the preclinical work. James showed the proof of concept in the clinic. This is, as he said, the first time that RNAi has been used directly to the lung and is able to achieve significant target engagement. Matthias put all this in context in the clinical context. My, my task today is to give you an update of the clinical programs and where we're going from now. Before I do that, I wanted to share why we're so excited about that, and I've been thinking about this since we started these pulmonary programs the last, you know, couple of years. You know, in chronic pulmonary diseases, there is really three fundamental mechanisms that cause or are associated with most of those chronic diseases. The number one is inflammation, the other one is mucus obstruction, and the third one is interstitial lung diseases. Those three mechanisms really explain the underlying pathophysiology and or the clinical syndromes of most chronic pulmonary disease. What we have right now with our three first trigger of drugs is that we're addressing each one of those. The first one, as you hear, for inflammation, is RAGE, ARO-RAGE. What is important is not just that we pick, I think, a very important target gene, but this drug does the effect in the right cell type, where it should be, which is the epithelial airway and alveolar cells. That's number one. The number two is the mucus obstruction. The target we selected is MUC5AC or ARO-MUC5AC. You need to have an effect in the goblet cells of the airway, not necessarily in the epithelial cells, and that's exactly what we're seeing. Finally, and importantly, when we look at interstitial lung disease, the alveolar epithelial cells is the key targets that we need to address. Again, the MMP-7, I think, seems to be a very validated target. When I look at all this together, I really get very excited about how we can address, with three genetic targets, a large number of pulmonary diseases. I will get back to this concept towards the end of this talk. Now let me get into the clinical programs. The first one I want to address is RAGE or ARO-RAGE. As you know, we started this program about two years ago or so. We demonstrate clear proof of concept of target engagement in more than one animal model. We evaluate the pharmacologic effect also in animal models, and we have short-term toxicology that enable our phase I program. We completed or almost completed the healthy volunteers component of the ARO-RAGE phase I study. We addressed target engagement, as James presented, and we have an initial read on safety that looks good. Also, we're starting the patient portion of this study, and we are completing the first cohort, moving to the next one Again, the goal here is to really demonstrate the target engagement in patient population and start to really identify what is the right dose and the right dose interval. Of course, safety is critical as well. What's the next step? The next step that you will see this year is the chronic tox data that will be available likely at the end of the year. The proof of concept with regard to the anti-inflammatory effect of the inhaled ARO-RAGE on top of the target engagement, of course. Finally, next year, we will start our phase II-B study to hopefully phase III program. as james said, we are adding two new cohorts in phase I aro-rage study, and the reason is because we really wanted to demonstrate the anti-inflammatory proof of concept before we gave into the phase II-B study. we're adding these two cohorts of patients with asthma and high FeNO baseline to really investigate where we have a significant effect. Why we believe that that will be the case? Well, FeNO is really driven by mainly IL-13. We have significant data in different animal models, both in mice and rats, showing that either knockout RAGE or inhibit RAGE production with an RNAi trigger, it really decrease IL-13 or prevent the increase in IL-13 to an allergic stimulator. We have the preclinical proof of concept that, in fact, RAGE inhibition inhibit IL-13, which is what drives allergic inflammation, manifests biochemically as FeNO, as a biomarker. The other point that is important is two drugs that have been approved, biologics, and they are effective in treating allergic asthma, did show significant reduction in FeNO. The proof of concept that a reduction in FeNO should translate into clinical benefit has been established with these two clinical programs. This is happening as we speak. The protocol amendment is almost complete. This study is now conducted not just in phase I clinic, but in a large number of sites in different countries. We aim to complete this enrollment within the next few months. Where are we going from here? As you know, phase I study will be completed next year. We will have a good idea about the dose interval, safety, and proof of concept of the anti-inflammatory or anti-allergic effects. We need to get phase II study. the clinical development path in severe asthma has been established by the biologic recently, and we will follow a similar pattern. The first next step will be to conduct phase II-B study. One of the key questions is what the patient population will be. We wanted to address both the T2-high and the T2- low, and we do that because we're following the biology that was described earlier today. The phase II-B study in severe asthma is about 500 patients. The endpoints are exacerbation, pulmonary function test with FEV1, and of course, symptoms and quality of life and PROs. Of course, the decision we need to make is whether phase II study, the primary endpoint will be exacerbation or FEV1. The implication of that might have to do with patient selection and size of the study. Initially, we will focus on asthma with ARO-RAGE, but as Matthias mentioned, ARO-RAGE and inflammatory, of course, has a significant role in COPD and other diseases as well. Now, let me switch over to MUC5AC and why we think this is really another important target and why we are prioritizing right now COPD as the first disease that we want to address with this drug. COPD is a very frequent, very common disease, about 16 million people. Nine of them have a phenotype of chronic bronchitis or hypersecretion. Of course, this disease decreased life expectancy and also has significant impact in quality of life and living. The current therapy has been the same for many, many years, LABA, LAMA, so bronchodilators and steroids, so inhaled steroid. Recently, as you see, there was a first proof of concept that a strong anti-inflammatory drug can be effective in a subgroup of those patients. Again, these patients have significant morbidity and the clinical trials, again, will be following the current guidance, which is about exacerbation, pulmonary function, and patient-reported outcomes as well. James already presented or showed you the key features of phase I study, and the news is that we're adding these two cohorts of patients with COPD, and patients particularly with a phenotype of chronic bronchitis and hypersecretion. This is critically important to us because of all the reasons that you heard today about how to assess mucin and MUC5AC in normal healthy volunteers. The protocol is complex for normal healthy volunteers because in order for them to produce mucus or produce sputum with this sequence of nebulization with saline and hypertonic saline in order to generate more mucus. Even if you generate more mucus in these normal healthy volunteers, it will be driven mainly by MUC5B. Of course, it's not the best model to assess target engagement, and that's why we're adding on top of the severe asthma populations, the COPD patients. This, this protocol amendment is going on right now, and we expect to have data on this early next year. Why COPD again is important here, clinically, COPD, and particularly those patients with hypersecretion, has significant symptoms and impairments in quality of life that are related to the hypersecretion. When you think about cough, when you look at the three of the more frequently used patient-reported outcomes instrument in COPD clinical trials and clinical practice, all of them highlight as one of the key issues, cough and the amount of phlegm or sputum that this patient produces, and how that impact the daily living activity. Clearly from the clinical point of view of improving patient syndrome, patient symptoms, and life, reduced mucus seems to be a very good idea. It's also important mechanistically, and this was already presented or described by Matthias. Of course, having obstruction in the airways is a bad thing. Having accumulation of this mucus is a plaque harbor bacterias, meaning it's an environment where bacterias can overgrowth. That's one of the reasons why people with COPD tend to have chronic or repetitive infection that cause exacerbation, that cause progression of the disease, worsening of symptoms, and so forth. This is a cycle, a vicious cycle that the accumulation of mucus is responsible for. The other thing that's important from the clinical and clinical development perspective is that. Right now, we have CT scans that can really describe and quantify the amount of mucus obstruction or mucus plug that you can see in patients with COPD or patients with asthma or any mucus obstruction disease. That helps from the diagnosis perspective, for the perspective of selection, patient population that more likely will be a good candidate for this intervention, but also speak to the severity of the disease. Because, you know, the whole function of the lung is to allow the air goes through, get into the alveolus, and do the gas exchange. Picture if you have this type of obstruction, the pulmonary parenchyma, distal to the obstruction, is not really working. How critical is to be able to prevent the progression of mucus plugs and mucus obstruction for the future of the disease, for the prevention of disease progression and also improvement of the symptoms? How we're gonna move forward here? We are gonna complete the phase I study. We're gonna have the data and target engagement and the initial clinical read, and then phase II-B study in copd. this is also being well described, and we can follow the path that is established already. The endpoints will be FEV1, exacerbation, and of course, patient-reported outcomes and quality of life. We will focus initially on those patients with hypersecretion, so the chronic bronchitis phenotype of MUC5AC. The typical size of this study is about 500 patients, and as you know, there are many of these patients out there. We will effectively learn about pulmonary function, exacerbation, and everything that will lead phase III study design. so again, I think I mentioned most of lead to phase III study. I think what is important is we will eventually address other muco-obstructive disease, and I think that's also a key feature of ARO-MUC5AC, and we'll get back to that in a couple of minutes. Finally, I want to mention ARO-MMP7. Again, this is our first drug that is aimed to address interstitial lung disease. The first one we want to address is, of course, IPF for idiopathic pulmonary fibrosis, because there is a lot of data that documented that this pathway is likely to be very relevant. One point I want to make that I think is very unique and important is we're targeting the alveolar epithelial cells because that's where this disease starts. In contrast to the approved drugs that mainly focus on TGF-β or fibroblast actions. This approach could be synergistic, could be used in association with whatever is the clinical standard of care, and that is really relevant as you think about such a severe disease that is almost universally fatal and that the current standard of care, even though has a number of limitations, both based on the efficacy and also on the tolerability due to adverse effects. Having a development of a drug like this that address the disease from a different mechanism, different administration path, and also that can be associated with what it is right now, the approved drugs of the standard of care. Our initial clinical view is to go into IPF. The phase I study that just started has, of course, normal, healthy volunteers. Again, this is phase I study where the patient cohort will be really important because that's where MMP7 is upregulated. We expect to see target engagement when we get to the patient population within phase I study. I also want to mention that we start to do the research and investigation to identify other interstitial lung disease where this intervention could be beneficial. I want to finish how to catch up where I started by saying that we're looking at three different gene targets in three different cell types within the lung, and each one of them have kind of a pipeline of diseases that we can address, not just the first one that we're focused right now, which is asthma for RAGE and COPD, MUC5AC, and IPF for MMP7. As you can see, the mucus obstruction component is important in a number of diseases, and we will eventually try to address most of them. Thank you very much, and now I think we will invite the speakers to have a Q&A session. Thank you, Javier. We have about 10 minutes or so for questions, after that, we'll do a short break. Hi, this is Prakhar from Cantor. Maybe first, a clarification on the addition of high FeNO cohort. Are you seeing more patients on the moderate end of the T2 spectrum in the initial asthma patients, and that is why you're adding this cohort? If I remember, you had a cutoff of blood eosinophil greater than 200 in the asthma patients. Any clarification there? The clarification is that this is a new cohort that we're including in order to have proof of concept of the anti-inflammatory, anti-allergic effect. When we designed the study, initially, we weren't focused on that. We wanted to have target engagement and initial clinical read, so we decided not to do the FeNO subgroup at the beginning. We realize now that it's really important and will add value as we're waiting for a much larger and phase II-B study. One for the doctor. Where do you think a target like RAGE fits in relative to the biologics that are out there, in the context that biologics can be spaced out to four to eight weeks, so maybe the dosing frequency is not that much of a differentiator? Any comments there on the residual unmet need? I think there are two things. Number one, you can address issues that the biologics are not addressing right now. That's one of the issues. Number two, you know, the dosing is high dosing in longer intervals, but in the inhaled medication here, rather than injections, even though some of them can be done at home, the inhaled medication is easier, and it gets spaced out much more than that, with not higher dosing. It's what disease are you addressing and where is actually not really a playing field for the biologics right now. Second, the spacing alone is not necessarily a big deal, but it's longer in inhaled. Patrick Trucchio at H.C. Wainwright. Just a couple of follow-up questions. The first one is, earlier you mentioned that the FeNO reduction of 42%-47% with the biologics. I'm wondering if you have an idea of what the reduction would look like for ARO-RAGE. What could this generate? Is this the data that's expected to be collected with the initial readout? Also, how does the FeNO reduction correlate to the reduction in exacerbation or other approvable endpoints in asthma? Separately, related to ARO-MUC5AC, how are you going to be evaluating the initial target engagement with ARO-MUC5AC in COPD patients, and is that the data you expect early next year? All right. The first question, what we expect to see with this ARO-RAGE in term of the decrease in FeNO, we're expecting to see something very similar. We know that FeNO is driven by IL-13 and the allergic reaction to that. We had a proof of concept in preclinical animal, but in two different models, the inhibition of RAGE clearly suppress IL-13. The translation of that should be a decrease in FeNO. When you look at, the magnitude of IL-13, you know, I think it's likely to translate to that. I wouldn't say that, it is true across the board, and maybe Matthias can speak to that, all biologics decrease, FeNO. Definitely the two that I presented here, dupilumab and tezepelumab, did decrease FeNO significantly in the 40%-50% range, and that translate into clinical benefit, both in pulmonary function and also in exacerbation. Whether the magnitude of FeNO decrease relates to the clinical benefit, I don't know, but the FeNO is a specific feature of those patients with allergic asthma or T2- high, and in those patients is where you see the maximal clinical benefit on these anti-inflammatory drugs. I think at this point, I feel comfortable with making that translation, but I don't know, Matthias, if you have. Yeah, I feel comfortable with that as well. You select people with high FeNO, right? I mean, it's a special population. The hope here is, you know, the expectation is that ARO-RAGE is going way beyond that, you know. The question is, what are the biomarkers? That's a different question. Then finally, about COPD and MUC5AC. Again, MUC5AC is upregulated in patients with a disease situation. It can be severe asthma, it can be COPD, bronchiectasis, or no CF, or CF bronchiectasis. That's a fact, and it's a magnitude of order, more than one magnitude of order of increase in MUC5AC expression. When I say that, is if you picture the mucus of a normal person, it will have a minimal amount of mucin that is produced by MUC5AC. In contrast, in patients with COPD or severe asthma, that's the opposite. Number one, they produce a lot more mucus than a normal, healthy lung. Second, that mucus component of mucin is driven MUC5AC. We are very confident that we're gonna be able to describe target engagement, in part because also the assay is behaving very well, and we're working on that. We don't have an issue right around the assay. The issue is we're not having samples that have enough mucus and mucus that have enough mucin driven by MUC5AC. All that will be reversed when we study patients with COPD. Thank you. Oh, great. I have a few questions. Maybe the first one, on αvβ6. Can you just talk about the safety risks associated with that? Obviously, Morphic Therapeutic has a paper out there suggesting bladder cancer signaling their preclinical data. They actually argue that that is on t arget. I think Biogen used to have monoclonal antibody that was ultimately discontinued. What gives you confidence that you can actually engage αvβ6 with no major safety issues? That's one. Two, if I recall it correctly from last year, you were also planning to measure RAGE in sputum. I don't know if I've seen the data today, so wondering if you have any update on that, and if you could comment on what you're seeing there. Lastly, on the relative potency, it looks like you're using higher doses for MUC5AC versus RAGE. Can you just talk about the relative potency between the two triggers and maybe bigger picture, what gives you confidence that you can actually get a pretty good therapeutic window for MUC5AC, despite higher doses? Thank you. Sure. I'll start with the platform, the αvβ6 integrin targeting. you know, obviously, this is a delivery receptor. We're seeing transient internalization of the receptor with periodic dosing of monthly to two monthly, every other month, something like that. Small molecule inhibitors that are intended to really affect the pathophysiological pathways that might be driven by this receptor require 24/7 dosing, BID dosing, and full coverage there. We're aware of these pathways. We've looked downstream. We've looked for alterations, potentially in TGF-β, signaling the most sensitive readouts there are phosphorylation status of Smad2 and Smad3. We've looked at that. We see no evidence of that changing. As a delivery receptor, we're quite confident that that's not contributing to any problems there. I think the next question was a clinical question. Sputum. Sure, yeah. The sputum, the question on sputum RAGE, we don't have all the sputum RAGE data yet. I think, similar to the situation with MUC5AC, I think RA GE in the sputum, in the healthy volunteers, at least in the sputum, has been sort of inconsistent. I think the serum and the BALF, what we're seeing there, both in the placebos and in the active expression, is really consistent. I think those are the best biomarkers we have. The other question was on MUC5AC dose. I me an, I think the doses are similar. There's some difference between between the two and, you know, clearly with RAGE, we're seeing proof of target engagement at those dose levels, I would expect that to translate into other programs as well. Mayank from B. Riley Securities. Good to see first asthma patient data today for ARO-RAGE. You also touched on the NHP data where, you know, you showed the BALF lowering relative to serum RAGE. That phenomenon of, you know, comparable pharmacological effect, could you talk about, you know, as you look to generate additional patient data for higher cohorts, any early thoughts on what lowest therapeutic dose could look like and what sort of frequency, you know, you could be targeting? The follow-up question I had also in Q4, you will have the chronic GLP tox data for ARO-RAGE. Wondering, you know, how that reads into the other programs that I'm assuming you're also running chronic GLP tox for other programs also. How does that read through into other programs? Yeah, sure. I'll take the last one first. I mean, I think we'll see what the chronic tox data show, and depending on the results, I think that would, you know, not definitively read on other programs. If we have the safety margins that we'd like to have, that would, I think, certainly be helpful for other programs. In terms of the question about the asthmatics and what doses might we see a downstream effect, I think that's why one of the reasons why we added the FeNO cohorts, to help understand how the knockdown levels at different doses translates into changes in markers of inflammation. We have FeNO to measure. We have other markers in the study, in the patient cohorts. What was the third part of your question? I think you addressed both. Just a follow-up for Chris, maybe. As you know, a company like Amgen also had to partner with AstraZeneca, you know, to sort of recognize the full potential of mepolizumab. I'm just curious, you know, how you're thinking sort of two, three, four, five years down the line of the broader portfolio at a program by program level, given the capabilities that you would need to, you know, recognize the full potential here. Yeah. As I mentioned, the pulmonary space is a target-rich environment, so we see a lot of drugs coming out of that. I do expect that we will do some partnering there. We are not interested right now in partnering these three candidates. You know, we're gonna continue to develop these, and we will bring more, you know, candidates into the clinic, you know, over the next several years. I don't know what we're gonna partner, but I assume that there will be some partnership activity in the pulmonary space, but certainly not everything. You know, We do expect to commercialize pulmonary drugs. Madhu Kumar, Goldman Sachs. I mean, a couple of questions for Dr. Salathe and also for the whole team. First, I mean, the natural question that comes up with all the animal studies is knockout zero, wild type is 100%. Where do you think the tipping point is? Like, where is it a level of knockdown that effectively represents complete loss of function of RAGE, as evidenced in the kind of efficacy data seen preclinically? That's always a very difficult question to answer, and I think there are a few considerations. Number one, a lot of RAGE is expressed in the parenchyma, in the alveoli. From an asthma and COPD perspective, at least for now, we're not really interested there, right? We are interested in the airway. So if our biomarker is RAGE, you know, if we don't knock it down in the alveoli a lot, whatever that means, right? We still see RAGE in the serum, even though we may have a complete knockdown in the airway epithelium. I think the answer to this can only be addressed with biomarkers and physiological responses. If you see these knockdown effects in the human beings, this suggests there is a broad coverage and knockdown of the RAGE, at least. I can't really answer, but it looks good to me because I would expect that the inhalation is mostly targeting the airway, less so the alveolar space. You know, obviously, we cannot really do lung biopsies, although you could, but that's very invasive. That would be the only way. I think the secondary is really easier to look at inflammatory responses and physiological measurements. I'm encouraged by these significant knockdowns. The question again, for Dr. Salathe, but also for the team. You've mentioned kind of the addition of this FeNO cohort. Makes sense in the eosinophilic disease. We know FeNO is a good biomarker. How are you thinking about biomarkers in the T2-low population? This is a neutrophilic population, something between you can knock down RAGE, and you can see a function on clinical outcome. Is there some kind of thing in between you can look at to say, "Hey, we're hitting the target enough to translate into clinical benefit? Do I go ahead? Okay. Now I'm going to set you off for something. We can see what I think. I mean, you can be invasive, and you can do BALs and look for cytokines and inflammation and cells. That's one thing. I also believe that there are now technologies to use, for instance, exhaled breath condensate, et cetera, to vary in low levels to actually measure previous activities, cytokines, et cetera, on a consistent basis. Some of that obviously needs to be developed further, but I think there are non-invasive ways to look at that as well. Plus, you can do the more invasive look at with bronchoscopy. Yeah, which I don't think we're going to do that in patients, the bronchoscopies, and we can explore some other approaches. Now, if you look at the precedent for the biologics, for some of the COPD-developed drug or the non-asthmatic drug, there isn't really anything like FeNO, which is very reliable, correlate with the disease, correlate with the mechanism, the underlying mechanism of the disease. I don't think that level of biomarker or surrogate exists for the non-type 2 or the COPD population. We will need to be more clinically based, and target engagement should be our lead indication to move on to the next level. Now, the good news is we're not going to wait until the very end. Right now, our plan phase II to include both populations and to power the study accordingly. One last one on the mucus depletion, the MUC5AC program. One can be the eternal optimist or the eternal pessimist on how you think about MUC5B and MUC5AC, right? You're right, the MUC5AC goes up a lot more on a relative basis, but there's just physically more MUC5B, and if that goes up, you can make the argument, look at the math you guys put up there, that most of it's going to be MUC5B still, even with the increase. As we think about muco-obstructive diseases, how much of it is about the absolute decline in mucin versus the quality of the mucin that's being targeted, where, like, depletion of MUC5AC is qualitatively different than depleting MUC5B or just total mucin? Okay, I'm going to take a stab at that, and I'm not sure how long it'll take. When you look at some of the work, I mean, MUC5AC to MUC5B ratio goes up, but you're absolutely right, 5B goes up as well. If you look at COPD patients, there is a increase in the mucus solids, meaning the combined mucus in that sputum as well. The problem with MUC5AC is that it's much more sticky. You know, it sticks to the airway epithelium itself. When you look at David Erle's paper that was mentioned once in the JCI, it actually doesn't even secrete fully. It's adherent to the cells and therefore has this plug capability that much less of an issue occurs in MUC5B. The idea is that if you then have this plugging, you also have secondary inflammation. If you can prevent the MUC5AC, you may still have a MUC5B elevation. That is a true statement, but it should be, and I say should, because that's difficult to measure, it should be clearable. The mouse is not really a good animal model for this because mice clear sort of with air-liquid interface without even coughing, et cetera. But if you don't have a sticky mucus that is adherent, you may also have a better cough mechanism to clear it out. That's the theory behind it. If you prevent mucus plugs, you get a decrease in inflammation as well, which helps you overall in terms of the MUC5B elevation as well. Great. Just a quick question. You mentioned earlier the dual trigger strategy and potential in lung. Does it ever make sense to combine RAGE and MUC5AC, or are these different enough patient populations where one or the other would be better served going after, the specific diseases? Thanks. As you saw, and I think in my last slide, we're going to target both these, let's say asthma and COPD as the two diseases with both drugs. Now, there is proof that an anti-inflammatory approach with biologic might help people with COPD or patients with COPD, and we think that mucus obstruction is a significant component, so both drugs might be developed for that single indication. The other concept clinically that is evolving, and Matthias presented, is that quadrant that shows that maybe the patients in the future will not just be divided by asthmatic or COPD, but based on the phenotype with regard to the immune component and the mucobstruction component of the disease. That could help clinicians to decide which is the best approach. Of course, there is overlap, and of course, today, both diseases are treated with multiple drugs that do different things. It's not unthinkable that at one point you can combine. Whether that will be part of our long-term dimer strategy, I don't know now, but it could be, because it's a really good point. Actually, just to be clear, the dimer data presented today was hepatic delivery, not lung delivery. Okay, we're running a little bit behind, so let's take a quick break. We were gonna do 10 minutes, but let's come back in five. Let's be back at 11:26 or so. Thank you. Just about to get started, so come back and take your seats, please. We're gonna bring James back up to talk about some of the earlier programs, the ARO-C3 and the PNPLA3 programs. We'll just briefly review some of the earlier-stage liver programs. First, starting with ARO-C3, which we're developing for complement-mediated renal diseases. Specifically, we're focusing on C3 glomerulopathy, which is a rare disease. There are only about 50,000 or so of these patients globally. However, half of these patients progress to end-stage renal disease within about 10 years. While transplant is an option in these patients, the disease actually recurs in the transplanted kidney in about half of those patients. There are no approved therapies for C3G, and we think that C3 is really an ideal target for this disease because it's the accumulation of the downstream C3 split products in the setting of overactive alternative pathway that really drives the pathogenesis of this disease. If you silence C3, you should be able to prevent the formation of those split products and prevent the downstream damage to the glomerulus. Similarly, IgA nephropathy is another area of interest. This is not a rare disease. There are over 1 million patients globally, and this accounts for about 40% of all cases of glomerulonephritis. This disease is also largely driven by overactivation of the alternative pathway of the complement system, and this is supported by biopsy evidence. Also, the increased amounts of C3 split products in the blood, that's actually prognostic in IgA nephropathy, so high split product levels means a worse outcome in these patients. Then also genetic studies, where variants, genetic variants that increase alternative pathway activity have a higher risk of developing IgA nephropathy, and those that decrease alternative pathway activity actually are protected from IgA nephropathy. Importantly, we think that urine protein reduction could be a pathway for accelerated regulatory approval in both of these diseases, and there's some precedent here for using proteinuria as an approval endpoint for accelerated approval, at least in IgA nephropathy. This is some of the data from phase I study. This was a healthy volunteer study of ARO-C3, and you can appreciate on the left, after a single dose, we're seeing 82% mean reduction at the top dose level. Again, this is C3 in the blood in healthy volunteers with good duration of about 16 weeks after the single dose. On the right, after two doses, up to 88% knockdown with also duration through about week 16. These levels of knockdown translated nicely into measures of alternative pathway activity, such as Wieslab AP. With the top dose level, we're getting up to 99% reduction in Wieslab on the left and about 91% reduction in AH50, which is a measure of hemolysis on the right. Far in this program, the healthy volunteer safety profile has looked good, with no SAEs or dose-limiting toxicity. Importantly, we've seen no evidence of infections with encapsulated organisms, which is important for complement inhibitors. The most common AEs are headaches, upper respiratory infection, and inflammation at the injection site. In summary, ARO-C3 has achieved knockdown of up to 88% in the blood, and we think the duration can justify quarterly or less frequent dose administration. The safety profile has been favorable, and the knockdown that we're seeing has translated nicely into reductions in measures of alternative pathway activity that we think are competitive with other alternative pathway-targeted therapies that are either approved or in development. Additionally, we think that the small, infrequent injections that we can use should have advantages over other alternative pathway inhibitors that require large doses, large sub-Q infusions, or even BID oral dosing. The patient cohorts are open in the phase I or phase II-A study. We have cohorts that are enrolling patients with C3G and IgA nephropathy. Moving on to PNPLA3, as you know, this is the program that we initially licensed to Janssen as part of our hepatitis B deal we did with J&J several years ago. This program will be coming back to Arrowhead due to strategic decisions at Janssen, not due to any issues or problems with the drug. We'll share some of the data here in a few slides. First, just to touch on the target. We really like this target. We think this was a great siRNA target. We thought it was a great target when we worked on this program years ago and did the licensing deal. Normally, PNPLA3 serves as a lipase. It sits on the surface of the lipid droplet in the hepatocyte and metabolizes triglycerides. In the setting of the I148M PNPLA3 variant, this variant codes for a non-functional protein that's resistant to proteasomal degradation. It just kind of sits there on the surface of the lipid droplet. It doesn't do much other than block other functional lipases whose job it is to metabolize the triglycerides in these lipid droplets. The lipid droplets just kind of get bigger and bigger. This leads to hepatic steatosis, downstream inflammation, eventually NASH, and liver fibrosis and cirrhosis. Since this is an intercellular target, it's difficult to modulate with an antibody, also difficult to hit with a small molecule because it sits. Again, it's an inactive protein. It doesn't have any active site or cleft or receptor for a small molecule to bind to. For these reasons, we think it's great for an RNAi approach, and we're not alone. There are several other competing programs that are in development, as well as the Arrowhead PNPLA3 program. The I148M variant is associated with not only increased liver steatosis that you can see here in the black bars. These are the homozygous patients that have fattier livers than the individuals who don't carry the variant or even compared to the heterozygous individuals. It's also associated with an increased ALT and an increased risk of not only NASH, but also NAFLD-related hepatocellular carcinoma. One of the most striking figures here, I think, is the increased risk in liver disease-related mortality in the homozygotes here at the bottom. The big gap on the Kaplan-Meier curve compared with even the heterozygous individuals that are closer to the top. We all know, there's a lot of NASH out there. NASH is, of course, very common. What is probably less well known is that this variant is also common, about a 45% allelic frequency, and so homozygosity as based on this common allelic frequency, it's pretty common to find homozygotes. There are about 12.5 million of these patients, homozygous PNPLA3 I148M variant patients with NASH, about 12.5 million of these patients in major pharmaceutical markets and about 4.5 million in the U.S. This is not a, some, you know, orphan disease, rare disease indication. This is really a pretty sizable, genetically defined population that should be amenable to an RNAi approach. This is the study that Janssen conducted. They had plans to do a single and a multiple escalating dose study. They stopped after the SAD component of the study. They enrolled NAFLD patients with high liver fat, so 8% or greater. They had to have a confirmed genotype, either heterozygous or homozygous, and they enrolled those separately, so they had heterozygous cohorts for the PNPLA3 variant and homozygous cohorts. The ALTs were relatively normal in this study. They excluded anyone with ALT at baseline greater than 1.5x upper limits of normal, and they excluded anyone with baseline liver fibrosis. Baseline characteristics here, I think the key takeaway is the level of liver fat in the homozygotes compared to the heterozygotes, at least in the U.S. population, the variant is very common in a Hispanic population. This is the key data takeaway. After a single dose at the top dose level, they were seeing reductions in liver fat using MRI-PDFF of up to 40%, and at the lower doses, you can see about a 20%-30% reduction in liver fat from baseline that has good duration. We're still, we're still getting the data from Janssen for the highest dose cohort, but at least at the lower doses, you know, a single-dose reduction in liver fat that's of 30% that lasts 24 weeks is pretty good. We would expect to see or hope to see the liver fat reduction at the 400 mg dose level in the homozygotes extend out here through week 24, but we'll have to get those data. In terms of safety, there were really no issues in the study, no adverse changes in triglycerides or in LDL cholesterol, no severe or serious AEs or adverse changes in labs or vital signs, and most of the AEs were mild. Importantly, in this phase I study after a single dose, although with long duration of effect, there were no, not a signal around GI toxicity or GI AEs. You know, not a lot of complaints of nausea, vomiting, the types of things that are commonly being described with some of the other NASH programs in later stages of development. We look forward to continuing the development of this assay. We're currently working on the design of phase IIa study that would enroll patients with NAFLD and high ALT at baseline. We could measure then, after multiple doses, changes in not only liver fat, but also changes in ALT and changes in other non-invasive measures of fibrosis and NASH activity. Things like FibroScan, ELF, PRO-C3. If this study looks favorable, if the results from this study are favorable, we would then progress to phase II-B study, a larger study with the typical histologically driven NASH endpoints. We'll pivot here from the early-stage liver programs to the cardiovascular programs, and I'll hand things over to Professor Goldberg. I'm having a little hoarseness in my voice, but I think I'll do fine. I wanna tell you a little bit about the kinds of things I see in the sort of lipid universe, something about an acute disease, and then a bigger picture about lipids and cardiovascular disease and what people who do what I do are thinking. We see somebody like this down on 34th Street about twice a month, somebody who has triglyceride levels that look like cream, or about 8,000 mg per deciliter, 8% fat. They get this finding called eruptive xanthomas, and if you look in their eyes, their blood looks like cream of tomato soup. These people get admitted to the hospital with inflammation of their pancreas called pancreatitis, and they spend anywheres from a few days to weeks in the hospital. It has a number of complications and is associated with mortality. It is the third most common cause of pancreatitis in the United States and is, you know, not a rare condition since we see it a couple times every month. Where is this fat or triglyceride coming from? It comes from two places. It comes from the fat that you eat. It gets reassembled in your gut, goes into your blood, and then circulates. It also comes from your liver, where it's basically re-put together from either fat that's made in your liver, which is adopted from carbohydrate that's converted to fat or from lipid that returns. Both forms of lipid that circulate in particles, either in chylomicrons from your gut or VLDL from your liver, require the same enzyme, this enzyme lipoprotein lipase, to basically degrade the triglyceride or liberate it and allow the fatty acids to get into tissues. You could see if you have a defect in this enzyme, your triglycerides go up and up, and if you have a genetic defect, they can be very, very high and cause a pancreatitis syndrome. This is the key to preventing triglycerides from getting up. If you get this enzyme reaction to work better, triglycerides will drop. There are two approaches now to lowering triglycerides, both of which really focus on that lipase enzyme. One is inhibition of a protein called ApoC-III, a small circulating protein that's on VLDL, chylomicrons, and HDL, on a lot of lipoproteins, and it's long been known to be an inhibitor of lipoprotein lipase. It turns out it also has other actions that block the uptake of lipid particles from the liver. The second approach has been to inhibit an inhibitor. There's an inhibitor predominantly made in the liver called angiopoietin-like protein 3, or ANGPTL3, that works as a complex in your bloodstream to actually block lipoprotein lipase. The other approach has been to inhibit the inhibitor. This protein also looks like it has other actions, and the other actions have to do with reducing LDL particles, and I'll mention that in a couple minutes, especially in the setting where the normal pathway, the LDL receptor pathway, is defective. Okay, the C-III. The story of ApoC-III actually came from a genetic study that was done now, I think it's like 15 years ago, down at University of Maryland, where they studied Amish in Lancaster County, Pennsylvania. The investigators found that there were Amish people who had very low levels of triglyceride, very low incidence of cardiovascular disease, and they had a defect in this protein called ApoC-III. Very quickly, a number of companies jumped on this, and they made ways to inhibit the ApoC-III, with the idea that they would inhibit the ApoC-III and triglycerides would come down, which exactly happened, thinking that ApoC-III was the inhibitor of lipoprotein lipase. Believe it or not, as somewhat of a control experiment, they actually reduced the ApoC-III. This was done by Ionis. They reduced the ApoC-III in patients who had enzymatic molecular defects in the lipoprotein lipase. It proved that the ApoC-III actually had another role, and that other role was to block lipid uptake in the liver. Even if you don't have any enzyme, this therapy works and will lower triglycerides, as you can see, about 80% in people with the rare genetic diseases where the usual therapies do not work. These are rare patients, and they're rare patients with the molecular defects in lipoprotein lipase or the other components of that system. More often, the patients we see with the really high triglycerides who come in, the more common things are somebody has diabetes, and they have a heterozygous defect, and you put diabetes or obesity or some other condition on top of a defect, and their triglycerides will go up very high, and those people are more common, the patients we see who come in with the high triglycerides and the pancreatitis. The rare molecular defects, well, they come to me, they are not generally what people see. The bigger issue for triglycerides is that almost 30% of the adult population has some degree of hypertriglyceridemia. Is that an issue? For over 50 years, since the time when I was a medical student, people would ask this kind of question. They would say: How important are the triglycerides for cardiovascular disease? Some of it was driven by things like this paper that came out in 1973 from a group in Seattle, that raised the question that triglycerides were as common an abnormality as high cholesterol in people with cardiovascular disease, at least in Seattle. This paper, by the way, was written by Joe Goldstein, who went on to win a Nobel Prize for describing the LDL receptor. Subsequent to this, there have been studies looking at how high your triglycerides go after you eat, so-called postprandial hypertriglyceridemia, just triglycerides and cardiovascular disease, and more recently, genetic abnormalities, all of which that raise triglycerides, are associated with more cardiovascular disease. What's missing? What's missing is an intervention trial showing reducing triglyceride reduces cardiovascular disease. If you followed this literature, this is the most recent attempt to do that kind of trial. This is the trial called PROMINENT. It used a new form of fibrate called pemafibrate, and this paper came out last fall in New England Journal. They looked at the right people. They were people with high triglycerides, many people with diabetes. I think most of them had diabetes. What they found was, even though the therapy reduced triglyceride levels, it did not affect cardiovascular disease. In fact, it was equipoise. Whether you were on the drug or you were not on the drug, you had the same incidence of cardiovascular events, or so-called MACE. What did this do? This trial, what it did, is it showed no overall change in cholesterol, no overall change in ApoB, even though triglyceride went down. What this trial did is it converted the triglyceride particle, it's called VLDL, into the cholesterol particles called LDL, and it was equipoise because this trial proved that the VLDL and LDL were equally atherogenic. Equally atherogenic. The problem was that the LDL went up during the trial. This is not the way to do it. Fibrates are not the way to do it. This may be the way to do it. We'll see. You'll hear more about this trial from Javier. This is what Arrow ApoC-III does, but lowering ApoC-III in general will do this. You can see a marked drop in triglyceride, 220 to 59, but you also, LDL does not go up. Actually, it goes down, and ApoB goes down. This is a different kind of approach and doesn't have the issue of converting one atherogenic lipoprotein into another. The second way to drop triglycerides is to use this other approach, ANGPTL3, and there's silencing RNAs and antisense that work for this, as well as monoclonal antibodies, and you'll hear a little bit about this. You have two different approaches or two different types of therapies. The ApoC-III works better in the rare people with the molecular defects, though, in the lipase cascade. What else is unmet? Mostly, we can take care of cholesterol pretty well. We put people on statins, ezetimibe. We now have PCSK9. Except for the-... person like this in the middle, who is a young person who has a homozygous loss of LDL receptor, and they get cholesterol levels of 500, 600, 800, 1,000. 1,000 is about as high as they go. They get palmar xanthomas, that's those things on their hands, and they could get myocardial infarctions at 15, 12, five years old, and bad aortic valve disease. We don't really have a way to treat them. They're treated with like a dialysis system. When I was at Columbia, we used to send these kids for liver transplants, which actually does work. What are they doing? They're missing the receptor, the LDL receptor, and that's why the drugs that mostly are require upregulation of the LDL receptor, that's how statins work and PCSK9. If you have no receptors, they don't work. ANGPTL3 does, and it's not clear why, but it's clear that this particular molecule activates some other pathway that we don't know yet, which is an alternative LDL removal pathway. This is a little bit of an unmet need. The last thing I think you should know about. Oh, I Oh, I went back. I got to go backwards 1. There we go. The last unmet need is this molecule called Lp(a). It's a risk factor. It's a small extra molecule stuck onto LDL. It's a potent risk factor. It's made in the liver, and it will be treated with a liver approach. What did I try to quickly tell you? C-III inhibition treats familial chylomicronemia syndrome, something we did not have therapy for before. Unlike fibrates, C-III inhibition lowers triglyceride, does not raise LDL. It may give us a different approach to try to answer the question, how important are triglyceride particles? ANGPTL3 is around, is another approach, and Lp is another thing that we will be treating probably in the near future. I'll stop with that. Thank you. I'll let Javier tell you about the programs here. Thank you. I want to start making a comment and similar to what Chris did at the beginning, saying that in six years, we brought about 18 molecules to the clinic, which is unheard of, and probably this is the only example. In the clinical development group, we took two molecules in three years from phase one to either phase three or enable phase three in three other indications. Two molecules, four indications, ready to get into final registration mode within the last three years. The, can I give you an update of the cardiometabolic program, both molecules, ARO-ANG3 and ARO-APOC3? You are familiar with these studies, the PALISADE study, the FCS study. We communicated a few weeks ago that we completed enrollment of that study, 75 patients. It's a one-year study, and we are already working on registration mode with many different aspects of what it will take to get to that point. The SHASTA-2 study of ARO-APOC3 in patients with severe hypertriglyceridemia. Of course, we completed enrollment last year, and I'm going to present now the final result up to the primary endpoint that was at 24 weeks. All 100% of patients complete 24 weeks in this study already. The newer study on mixed dyslipidemia, similar, we completed the enrollment, and we completed the week 24 data, which is the primary endpoint, and I will present this data today as well. On the VISTA program, which is the INHBE or the ARO-INHBE, ANGPTL3, HoFH, phase II study gateway is underway, but we already presented, I think it was last week or the week before in Europe, the results phase II study. again, we're already thinking about how to get this drug to the patients that need them. Finally, the ARCHES-2 study in mixed dyslipidemia with ARO-ANG3. Again, the study is complete. I will share with you the data on how we're thinking about moving forward. I'll start with the FCS. I will remind you something that you probably already know, which is we did study four patients with FCS in phase I study, 1001. It was a small group, only four patients. As you can see, this patient received 50 mg of ARO-APOC3 at baseline and at week four, and they achieved about 85% reduction in TG. A very similar magnitude of reduction that you see in the other group of patients that also has severe hypertriglyceridemia, but not the genetic component of FCS. We do have, in this case, I think, a significant level of proof of concept based on the mechanism of function and the initial data that we developed on phase I study. On the right part of this slide, I wanted to share with you the baseline characteristics of the FCS study that is fully enrolled. Patients in average were about 45, 46 years old, about half of them men. The median TG level, about 2,100, and that's expected. Genetically or clinically confirmed, of course, all of patients in order to qualify for the study had to be in either genetically confirmed, with that 44 of the 75 are genetically confirmed, then the others are clinically confirmed. This is important because. This was the outcome of our interaction with the FDA when phase III protocol, in which initially we were focused only on patient with genetically defined FCS. The feedback was like, there are a number of patients who have clinical feature FCS, based very high TG levels and pre-existing history of pancreatitis, theirself or family members. Those patients should be considered FCSs if that's the clinical feature, because some of these genetic mutations might not be known. We genotype all these patients, and when we get to that point, we will disclose that information on how the data looks like. Also importantly, and this is back to what Dr. Goldberg told us today, the instance of pancreatitis and severe pancreatitis in this population is very high, and that's the goal of therapy, reduce TG levels and prevent the event of pancreatitis. Now I will switch over to the SHASTA-2 study, ARO-APOC3 in patients with severe hypertriglyceridemia. We enroll in this study patients with triglycerides levels greater than 500 at baseline and no greater than 4,000. The key endpoints, of course, are all the lipids, target engagement as assessed by ApoC-III and mainly triglycerides, and of course, safety as well. We randomize the patient into 3 groups, 10 mg, 25 mg, and 50 mg at day 1 and at 12 weeks after the initiation of the study. Of course, we compare this with a group of patients on placebo for each of these subgroup. The baseline characteristics are as expected, patients in average, when you include patient with more than 500 of TG, the average is about 650 or 670, and it was well balanced across the different treatment group. This patient tend to have low LDL cholesterol, in the 60s, as you can see here. Again, all the other parameters are consistent. There were more males in this case. About 80% were males, 20% females, and the BMI is in the upper end of overweight versus obesity. Here are the two key endpoints on this study. The first one is ApoC-III, and you can see some level of dose response. The first assessment was at week four, and you already see a very significant decrease in ApoC-III, achieving the navy after the second dose at week 16, with a reduction of about 76% for the 10 mg dose, 86% for the 25, and 87% for the 50 mg. It's very consistent, the effect of 25 and 50 mg with regard to ApoC-III reduction. The same is true for the triglyceride reduction, which you see already a very profound effect with a dose as low as 10 mg, and then we see an increased efficacy at the 25 and 50 mg dose. The table here at the bottom of the slide shows the baseline level of TG that was about 670-700, and the post-baseline at week 16, that went from 696 to 150 approximately, and that was even more profound in the 25 mg, approaching 114 and even more in the 50 mg, 94. The normal level of TG, and I'm not talking about people with severe hypertriglyceridemia, but in general, it's lower than 150. The average patient or the average response, put this patient with very severe hypertriglyceridemia into the normal range. Another way to look at the magnitude of the efficacy and how we will translate into a clinical benefit is to look about the proportion of patients who at baseline have very severe hypertriglyceridemia. In order to simplify this, we selected those patients who at baseline have TG 880 or greater, which is the definition that people use in Europe. We wanted to use that to highlight that these people are at very high risk of pancreatitis. If you look at both the 25 and the 50 mg dose, at week 16, almost all patients are below the threshold at which pancreatitis occur. This is the clinical benefit that we want to demonstrate. There is not too many examples of a treatment that can achieve this type of efficacy that hopefully translate into the improvement in clinical outcomes. With regard to safety, and we presented this last year, there is really AE that are related to this patient population and comorbidities. There is a very well balanced between placebo and treatment groups. All the SAEs were not related to the treatment, and there was no patient who die in this study. The finding that we also reported last year is that in the 50-mg groups, a small group of patients who have uncontrolled diabetes at baseline, the inclusion criteria was up to 9% of HbA1c, so there was number of patients with poorly controlled diabetes. Some of them have worsening on that diabetes or in A1c, diabetes control. What we did with that when we came about this finding last year, is we amended protocol, because we noticed that there was no cases that the investigator adjust the diabetes treatment. We adjust the protocol to create flags that go to the investigator and say, "You know, you have a patient that have an increase in A1c more than a given threshold, and please consider to do something to improve diabetes care." That was twofold. One is assuring compliance with treatment or adjust the approach to treat diabetes in that particular patient. Once that happened, most patients decreased their HbA1c. I think that's a very reassuring point with regard to this finding we reported last year. How we're phase IIi program, and we're right now, we still working on the briefing document to engage with the FDA and the European Medicines Agency phase IIi registration program. we're thinking about doing phase III studies. The SHASTA- 3 study that will be really similar phase II study. patients defined by TG greater than 500. We aim to enroll about 600 of those patients and to have a randomization ratio of 3 to 1. Why? Because the main endpoint in this study will be TG level and the safety aspect of the drug. We want to enrich the number of patients on treatment to reassuring about the safety aspect of this drug as we move forward. It is also very important to address the clinical outcome in this condition, and that is prevent pancreatitis. We're gonna phase III study that will be enrich for patients who have high risk of pancreatitis, defined by having a TG level greater than 880 and a past history of pancreatitis. The fine-tune details of that is still underway, you know, the approach to this that is important is the primary endpoint for those study, which is TG, will be done at six months, that follows regulatory guidance. We have the opportunity for an early file, but also this program will document the clinical benefit of this intervention, both in prevention of pancreatitis and likely to improve quality of life and symptoms in patients with sHTG. All right. Now let me move on to the new study of the ARO-APOC3 study in patient with mixed dyslipidemia. You also are familiar with this study. We enroll patients with baseline TG between 150 and 500, LDL cholesterol greater than 70 mg per deciliter, and non-HDL greater than 100. All these patient had to be on optimal, steady statin therapy, so we have phase II reassuring that that was the case, and all those patients were on statin properly treated. Key endpoints are the typical PD value marker related to lipid profile and, of course, safety. We randomized patients into four groups here. One group received 10 mg, the baseline and day, and week 12. Another group, 25 at baseline at week 12, and the third group, 50 mg at baseline at week 12. The final cohort, we enrolled patients into a 50-mg dose every 24 weeks with the intention to see how long the effect lasts after the first dose. The baseline characteristic, as expected, based on the inclusion criteria, patient at baseline have a TG level of about 220, LDL cholesterol in the 100 levels, non-HDL about 150, and ApoB tracking close to LDL cholesterol. Again, all the groups were well-balanced across the board. Primary endpoint was ApoC-III reduction, and once again, you see this similarly to the other population, a dose-ranging effect on decreasing ApoC-III that goes from 69% at week 16 with a 10-mg dose to 90% with a 50-mg dose. Here in orange, you have the group of patients or the cohort that received 50 mg every 24 weeks, and as you can see, the effect doesn't seem to last as much as when you give it every 12 weeks. On the right-hand side of this slide is the triglycerides data, and again, consistently what we showed before, even though these patients have a much lower level of TG at baseline, about 230 or so, the decrease is about 60%-73% based on the different doses at either the nadir week 16 or at the end of the dose interval, week 24. We replicate essentially the same results that we did before in the SHASTA study. Here, the non-HDL data, which I think is one of the critical one and reason to believe in this, we see again a dose range in effect in which the 10 mg reduced non-HDL about 20%, 25% for 25 mg, almost 30% for the 50 mg. When we look at the LDL, we see no changes in the two lower doses, 10 and 25 mg, and we're seeing a decrease of LDL, 10%-11%, with the 50 mg every 12 week. Remnant cholesterol, again, this was calculated, but I think it speaks to the point that Dr. Gaudet mentioned between LDL and the VLDL particles as atherogenic lipoproteins. We observe a 50%-60% reduction in remnant cholesterol, which essentially is VLDL. Again, we see some dose response that is consistent at the nadir and at the end of the dose interval. ApoB is reduced with all doses, anywhere between 10% and 20%, so we also see a dose response in the context of decreases of ApoB. With regard to safety, you know, this behave exactly as the other study. These AEs that we're seeing are all related to comorbidity. There was no reported SAE that were attributed to ARO-APOC3. We did see a similar event with regard to the increase in HbA1c, as we saw in the first study. We applied the same protocol amendment, and we observed essentially the same phenomenon that patients tend to come back to their baseline A1c once they adjust the treatment or enhance compliance with the treatment. Yeah, Dr. Gaudet showed this data, and this is what get me really excited about this program to develop ARO-APOC3 for the treatment of mixed dyslipidemia and prevent cardiovascular disease. The way I think about that is look at the first row that represent the average value of all these lipoproteins and TG in a typical patient with mixed dyslipidemia, treated with optimal statin therapy. This is a large population that is already been addressed to a significant degree, the LDL issue, and they still have this profile. Once you intervene with an ARO-APOC3, ApoC-III go from 15 to 2. TGs, as you see now, is 59. The high level is, or the upper limit of normal is 150. Non-HDL is now 107 instead of 150. LDL decreased to 98. ApoB now is 75. Remnant cholesterol is extremely low, and HDL increased by 65%, so now this person will have a lower LDL and higher HDL. You see that, as a whole, and fast-forward five years, a person that had persistent cardiovascular disease and had this profile, versus a person who had persistent cardiovascular disease or high risk for it, and has this profile of atherogenic lipoprotein. This is exactly why we think that this drug deserves a proper cardiovascular outcomes trial to really demonstrate that treating this risk factor will translate into prevention and atherosclerotic progression and eventually cardiovascular outcomes. I also wanted to share with you that we're working now on selecting the clinical research organization, the CRO, and the academic research organization. That's gonna happen within the next few weeks. Yes, we are a mid-sized company, and we're getting ready to run this large study. ARO-ANG3, the ARCHES-2 study, mixed dyslipidemia. This study has exactly the same inclusion criteria as the MUIR study on ARO-APOC3. We randomized patients to three treatment groups, 50 mg, 100 mg, and 200 mg, based on week 12, and the endpoints are the typical for these type of studies. I will just summarize the data from the highest dose, 200 mg, to make it simple. Just too many numbers here. This is the profile that ARO-ANG3 offers in patients with mixed dyslipidemia. 76% reduction in ANGPTL3, 60% in TG, 18% reduction in LDL, 60% remnant cholesterol. Non-HDL went down by 36%, and ApoB decreased by 22%. Once again, you see a very favorable lipid profile, and we're still evaluating how to move this program forward, because really the data is very impressive as well. Importantly, we did not see any increase in liver fat or any issue with LFTs. In fact, liver fat decreased by about 30% in the 200 mg dose group. Again, the adverse event were exactly the same as we see before, really related to the comorbidities seen in this patient population. We did see a similar increase in A1c. The pattern follow what I just mentioned before. Now, Dr. Gaudet already talk about HoFH. It's a very significant disease. It's very infrequent, it's very rare, but those who have it have a very short lifespan, and this start in early childhood. The treatments are very complex. There is a proof of concept that inhibiting ANGPTL3 does have a very positive effect based on the antibody to ANGPTL3, and Dr. Gaudet present that data. We're really looking to see whether we can have an intervention that will be more friendly to patients, and particularly children, and as effective as this antibody. We phase II study, open label, patient with HoFH. In this case, they were genetically confirmed. We enrolled 16 patients. Finally, I think we're at 18, randomized to either 200 mg or 300 mg every 12 weeks. As you can see, a very significant decrease in LDL cholesterol. Patient have a, like, 120 to 170 mg decrease in LDL cholesterol. That's represent about a 38% to a 42% reduction, and this is, I think, very consistent with what has been shown with the antibody therapeutics. That's through both 16 weeks and 20 weeks. We're looking forward to continue this program. I wanted to finish again, like how I started and tell you where we are right now with the cardiometabolic program. FCS is on its way to registration. The study fully enrolled. Last patient, last visit will be in the second quarter of next year, and at that point, we will initiate the work to get to an NDA filing hopefully before the end of the year. We're already working not just in the clinical aspect, but in all the other aspects that are required to file a new drug. That, for us, of course, is the first time we're doing and we're very excited as a company to be doing this. The SHASTA study, I mentioned how we're thinking about the phase III. We're going to go to the agency within the next quarter to conduct the phase III strategy. the intention is phase III studies soon after we have agreement on the plan with the FDA and with the European Medicines Agency. Similar pattern with the cardiovascular outcome trial with ARO-APOC3. We're gonna stagger this by a few weeks to be able to complete the work and to have the briefing document proper. By that time, we're gonna have the structure in place to run the study. Once we complete the phase II, again, we're gonna start our cardiovascular outcome trials soon thereafter. Finally, ARO-ANG3. Right now we are moving the program on phase III registration study. this study or this program will start probably early in 2024. We are still considering how to move ARO-ANG3 in the other patient populations. With that, I'd like to invite now my colleague, Tracie Oliver, who will talk to us about the commercial opportunities. Thank you. Thanks, Javier. A couple of takeaways I want you to have from my presentation is, first of all, ANGPTL3 and ApoC-III are validated targets for the treatment of dyslipidemias. Our programs have been largely de-risked going forward. As you saw from Javier's presentation, for both ARO-APOC3 and ARO-ANG3, we are starting with really very ultra-orphan indications and then plan to rapidly move towards larger indications that have blockbuster potential. Also, I'll show in this presentation how we plan to differentiate ARO-APOC3, which will support a very strong value proposition for physicians and payers, but more importantly for patients. Finally, talk a little bit about how we plan to move forward in commercializing our first drug. This schematic shows, sort of how we think about the dyslipidemia market, where you start with, very high levels of LDL-C with, familial hypercholesterolemia or very high levels of triglycerides with, familial chylomicronemia syndrome, and where we think our drugs can, have the most impact. Right now we're targeting, FH for ARO-ANG3, and then, mixed dyslipidemia out to FCS with ARO-APOC3. These market segments combined represent about 43 million adults in the US, so very, very large markets. Eventually, although we will start, as I said earlier, with HoFH, about 500 people in the U.S., and FCS, again, about 500 people in the U.S. For ANG3, our focus, as Javier has said, is really on HoFH. It's an ultra-orphan indication associated with significant morbidity. As Dr. Goldberg has laid out, the efficacy of ANGPTL3 inhibition in HoFH has been well established by evinacumab. Where we see our product being differentiated is that our mechanism of action doesn't rely on LDL receptor activity, like the PCSK9 inhibitors. We anticipate we'll see a stronger and a more predictable response to ARO-ANG3. Relative to the other evinacumab, again, is we have a very small injection volume, sub-Q versus IV for evinacumab, and then versus the PCSK9 inhibitors, every quarter dosing versus monthly or every two-week dosing that you have with Repatha and Praluent. We see this product as being highly differentiated for this patient segment. We know that we have a lot of potential in refractory hypercholesterolemia and also mixed dyslipidemia, but I'm not gonna talk about that today. I'm gonna focus more on ARO-APOC3, which is furthest along in clinical development. As Javier said, we have completed our enrollment in FCS. This is an ultra-orphan disease associated with significant morbidity. Our PALISADE study is not limited to genetically confirmed FCS, which we see as an advantage. While we know that this will yield limited revenue just based on the size of the market, it will be an important indication for establishing us as a commercial stage organization. Because sHTG is somewhat related to FCS, we know that we'll be able to leverage a lot of our learnings and insights from the FCS market into the sHTG market, which is much larger, about 4 million people in the U.S., and a market potential of over $1 billion. Finally, going into mixed dyslipidemia, where Javier demonstrated earlier, we have impact on both triglycerides as well as LDL-C and ApoB. There is about 6-10 million people in the U.S. currently not at target for LDL-C and triglycerides. We have this unique opportunity to address this patient population because of our ability to lower triglycerides, ApoB, and LDL-C while increasing HDL-C. We are planning a CVOT trial, and again, the potential in this market is over $1 billion as well. If we look at how we're gonna differentiate ApoC-III, really, we're focusing on a couple of different areas. where we're moving beyond just reducing triglycerides as a surrogate biomarker to really establishing clinical outcomes associated with reducing those triglyceride levels. As I said earlier, our PALISADE study in FCS includes both genetically confirmed patients as well as clinically diagnosed patients. Patients with triglyceride levels greater than 880 mg per deciliter and a personal or familial history of pancreatitis or hospitalization due to abdominal pain. This is different from the other products that are currently being studied in FCS. I think what it probably means for us is that we will have a broader patient population eligible for our therapy when we finish the study. Dr. Goldberg and Javier both spoke about hypertriglyceride-associated pancreatitis. This is a real risk factor, a real risk for patients with triglyceride levels greater than 500. I know that this graph is a little busy, but what I want to show is that the darker blue colors are the higher triglyceride levels, and these are patients who have had 1 episode of pancreatitis in the previous 12 months, or more than two episodes of pancreatitis in the prior 12 months. What you can see is that there is an increase in the incidence of pancreatitis as triglyceride levels go up, but it dramatically increases in patients who have a recent history of recurrent pancreatitis. The study that we're planning, the SHASTA- 4 study, will move beyond just showing that we can lower triglycerides, but hopefully show that we have a clinical impact on patients by reducing triglyceride levels. As Javier showed, the vast majority of patients actually shift to the left to have triglycerides less than 500 mg per deciliter, which puts them below the threshold at which pancreatitis is associated. Also, again, this is hard to read, but what I want to impress upon you is, it's not just pancreatitis that is impacting the morbidity of patients. These patients with high triglycerides, be it severe hypertriglyceridemia or FCS, have significant burden of illness, and each of these bubbles represents a symptom. The size of the bubble represents the proportion of patients who report this symptom, either from a daily basis to a monthly basis. What you can see is there is a vast number of symptoms impacting these patients, physical, emotional, and cognitive. Patients experience abdominal pain, joint pain, nausea on an almost daily basis. They worry about food. I don't know what you guys had for breakfast this morning. You probably exceeded the daily fat intake just with your breakfast that an FCS patient can have. They worry about food, they worry about the next episode of pancreatitis. They worry about if somebody else has prepared their food, how much fat is in that, in there. They suffer from depression, social anxieties because they don't want to go out and be with other people doing the things that people normally do, like have a beer and a pizza. Finally, cognitive symptoms. They report this sort of, this what they call a brain fog or impaired cognitive thinking. By adding in patient-reported outcomes to our studies, we'll be able to hopefully address these physical, emotional, and cognitive symptoms associated with elevated triglycerides in these patient populations. Finally, our CVOT study will really look at the sort of cumulative impact of ApoC-III on the lipid and lipoprotein profiles by reducing the residual risk posed by these atherogenic lipids and lipoproteins. We're really excited about the CVOT study because we believe that reducing triglycerides, LDL-C, and ApoB will result in a positive study. Oops! Finally, just a quick note on where we're focusing our attentions right now. I've talked about how we plan to differentiate ARO-APOC3 in terms of generating early clinical outcome studies, outcomes with pancreatitis, as well as the cardiovascular outcomes study. We're preparing the market. There's a tremendous amount of clinical inertia and misunderstanding about triglycerides, and one of our physicians called triglycerides, the Rodney Dangerfield of lipids. It gets no respect. Just educating physicians on the impact of high triglycerides and increasing the urgency to reduce them will be a key focus for us, as well as working with payers to understand the risk posed by high triglycerides and developing a compelling value proposition that will support reimbursement and access. Finally, we're preparing the company for our first launch. This is very exciting as we move from a clinical stage company to a commercial stage company. We are in the process of hiring out our commercial team, as well as medical affairs teams, expanding all of the internal capabilities across the key functions internally. We've been thinking a lot about our go-to-market strategy for U.S. and ex-U.S. We have not finalized it yet, but what we're trying to do is build into it optionality so that we can take what we're doing in the U.S. and leverage it where possible, ex-U.S. We're also gating our investment to major milestones, such as reimbursement in the E.U. market, as well as new indications. You'll see us grow from a small organization to a much larger organization as the market dynamics change. That is it for me. Chris? All right, we have done our best to exhaust you. I have a handful of slides, and then we'll be done. I think the update today represents a ton of potential value. Our late-stage clinical programs are moving rapidly towards commercialization. You know, these are ARO-APOC3, ARO-ANG3. We didn't talk about fazirsiran, we didn't talk about olpasiran, but those phase III studies. our earlier clinical stage programs are showing promise and a clear path, as represented here by ARO-C3 and ARO-PNPLA3. C-III has multiple indications we can go after. Data so far look compelling. PNPLA3 is I think, the only truly genetically validated, genetically targeted approach to at least a population of NASH, and we are excited about that program. Our pulmonary program appears to work, that franchise appears to work. ARO-RAGE is seeing up to 95% knockdown. We expect ARO-MMP7 and ARO-MUC5AC to follow, and we expect a large number of additional targets to follow after that. Platform expansion continues. We didn't talk about skeletal muscle today, but we expect to either partner ARO-DUX4, or file a CTA over the next month or so. We expect a CTA for our next skeletal muscle-targeted program by the end of the year. CNS is an exciting place to be. There are a number of good targets. Our preclinical data are quite good. We're excited about getting into that space, and I expect our first CTA over the next couple of months. CNS with systemic delivery is a truly transformational thought. Our early data are compelling there. We are looking forward to continuing to develop that and seeing if we can make it into the clinic with that sort of approach. Finally, adipose. This is the largest endocrine organ in the body, and we see a ton of interesting new targets there. So many of the areas that we are addressing have been neglected in the past, but are now sort of back in vogue, and that's not strategic on our part. A lot of that is just good luck, I think. Cardiovascular disease is one that has been avoided for years because of the cost associated with a CVOT, the length of a CVOT. Given the continuing risk factors, given new GWAS analysis, there is new interest in the space, and we are, of course, addressing that with ARO-APOC3 and ARO-ANG3. NASH. NASH was hot till it wasn't. It's a very large opportunity. It's a very large problem. Turns out it's a very difficult disease as well, and it is probably heterogeneous. We have recently seen promising data, and I think the market is back to being interested in NASH. Again, PNPLA3, I think, is a very unique approach to a subpopulation of NASH. Pulmonary. You know, there have been very few inhaled drugs ever approved by the FDA. It's been a very difficult space to be in. It is clearly a space where there is an awful lot of opportunity, and we are there now with ARO-RAGE, ARO-MUC5AC, ARO-MMP7, and more going forward. CNS, as we talked about, is a place where people were not jumping over themselves to make bets because it was such a difficult space. Recent data have been encouraging, our non-clinical data are encouraging. We are excited to be there. Finally, adipose. Again, the largest endocrine organ in the body. You know, if I was here talking about an obesity drug six years ago, no one would've listened. This is an important problem, and I think that being able to address adipose tissue enables us to get into that space as well as other metabolic conditions. We mentioned, you know, early on in the presentation today, we mentioned about the last 6 years, and so what about the next six years? As we talked about, you know, the six years between 2017 and 2023 have brought, or will have brought 18 clinical candidates into clinical studies. We think during the 6 years from 2023 to 2029, we'll bring an additional almost 20 new drug candidates into clinical studies. Given that RNAi is an increasingly validated technology, and given that TRiM is an increasingly validated set of platforms, we expect the majority of these around 40 drug candidates to actually make it to a patient. I'm reminded of when Elon Musk and Syndicate acquired Twitter, and I didn't follow this, but I heard about it. I think I saw a picture of it. He had a video of him walking into Twitter headquarters with a sink, and the caption was, "Let that sink in." Well, let that sink in, you know. We are not a large company, and we're talking about over the course of a fairly short period of time, upwards of 40 individual clinical candidates in clinical studies, and the majority of those making it out into patients. It's astonishing, and it is an exciting place to be, entirely. We don't look to benchmarks. We look to be the benchmark. What about the next six years? We expect multiple product launches, spanning small and broad markets, in different therapeutic areas, via wholly owned and partnered assets. We expect dozens of drug candidates in clinical studies spanning early to late-stage development across different therapeutic areas, both wholly owned and partnered. We are really a different kind of biotech company. How do we pay for all this? Well, there are multiple capital sources that we'll be tapping to reduce the long-term cost of capital. Certainly equity, you know, the selling of common stock, you know, is common in our industry. We have been judicious in this. We haven't raised money in about 3.5 years. I think we'll continue to be disciplined in this approach. Business development has been a big thing for us. Over the last six years, we've brought in almost $1 billion of capital from business development opportunities. We will continue to do that. I think that grows. You know, not only, you know, will we be doing around a deal a year, I think, going forward, but our existing deals, as they mature, will be bringing in additional capital, you know, as those milestone payments get larger. Debt, I think, is something that we can consider going forward. You know, we are approaching the state in our company where we can tap the debt market. Creative sources via product financing or even royalty monetization, as we did late last year, is an opportunity. Of course, commercial sales. We expect to be commercial in the next few years. With that, thank you for your endurance, and we can open this up for questions. Yeah, go ahead. You, Jason, go ahead. Hi, Prakhar from Cantor. On ARO-APOC3, on the diabetes event, specifically for the 50-mg arm, how many patients had diabetes at baseline? Were there any imbalances between the dosing arms on patients with baseline diabetes, given the higher events? Do you plan to take the 50-mg dose forward? About 60% of patients of this type had diabetes at baseline, so a small fraction of them had an excursion with HbA1c. It wasn't the majority, it was the minority of those patients, but it was different than the placebo group. With regard to... the second part of the question was? Were there any imbalances? No imbalances, no significant imbalances at baseline. These studies are relatively large and properly randomized, so randomization works. Whether we go with 50 or 25 mg, we're working right now on that, both from the pharmacology perspective in terms of doing the modeling and population PK, PD modeling. Also in the end, it's a clinical adjustment. We need to look at the benefit, we need to understand that, talk to our colleagues and experts to really decide which one is the dose that provide the best benefit risk for patients with mixed dyslipidemia. Will Pickering from Bernstein. For your cardiovascular program, could you describe the rationale for prioritizing ApoC-III rather than ANGPTL3 and mixed dyslipidemia? Just looking at the impact on LDL and TG, it looks like it's a bit more balanced in ANGPTL3. Then in sHTG, could you share your expectations for prior auth requirements in that indication, and whether we can expect something kind of challenging, like in the early days of PCSK9? Thank you. All right. With regard to why we selected ARO-APOC3, we think that the profile that ARO-APOC3 deliver is incredible for patients with mixed dyslipidemia. That does address that residual risk. Does ARO-ANGPTL3 does something very similar? The answer to that question is yes. Can we do two cardiovascular outcome trial? The answer to that is likely no. We're thinking about how to move that forward because that drug has a very profound effect in lipids and lipoproteins and atherogenic lipoproteins. We need to think about, we have an indication for refractory hypercholesterolemia, for heterozygous, familial hypercholesterolemia, and how we go into the major indication eventually. You know, those are choices you need to make sometime. We have two very good drugs. Both of them address what the medical need is in the residual risk of cardiovascular disease once you have LDL control. I think that may be part of the explanation, that we are focusing beyond LDL. You want to add? I'll do it, yeah. In terms of prior authorizations for sHTG, that's always a risk. We know that payers are always trying to reduce costs as much as possible, which is why we're really focused on demonstrating not only just a lowering of triglycerides, but also the clinical benefit associated with that, with reduction in incidence of pancreatitis, and then obviously with the CVOT study. At the end of the day, who knows what they'll do, whether they'll do step ads, prior authorizations, but what we're doing is trying to put together the strongest value proposition that we can to avoid that. Joel Beatty from Baird. For the ApoC-III CVOT, what relative risk reduction do you anticipate? The one that you need to get the valuable drugs. When you look at what is out there, you know, we have now every single cardiovascular outcome trial in our working space, starting with the four A study, and I was in medical school when that happened, or maybe I was in the residence already. You know, I always look at that because that was the number one or the first study that actually showed that reducing LDL translate into clinical benefits, and that was in about 30% or 35% reduction in people with persistent disease. Since then, we have many statin drugs. You have PCSK9, and if you look phase III study, the reduction was about 13% or 14%, and they need 27,000 patients. Whether that has to do with a shorter relatively study, with the patient population they selected, we don't know. I hope to see more than 20% risk reduction. I'm thinking right now. I don't know if, I don't know you want to make any comment about that? No, no, it's a very complicated calculation. The study is just high level. It will be an event-driven trial. The main work that we're doing now, and Dr. Goldberg is helping us with that, is to really select the patient population, to really understand who are the patient population, that the profile of ApoC-III will change their cardiovascular race. That is number one. And of course, from there, to assess the effect size is something that we're working on. We're doing some modeling work to try to estimate the event rate based on that population we select and the potential effect size. Again, the study, as most of the study, will be an event-driven study, so I hope we get it right. Hi, Madhu Kumar, Goldman Sachs. One really granular question about SHASTA-4, and then a bigger picture question about ApoC-III and hypertriglyceridemia. In SHASTA-4, you mentioned the idea of patients who have prior pancreatitis. Is it one event, two events, or do you have that kind of sorted out yet? A kind of bigger picture question, really for Dr. Goldberg, is as we think about the use of this drug in severe hypertriglyceridemia, what do you think it'll take, not for people like you, but for like Joe and Jill Schmo, practicing physician, who sees a patient who has very high triglyceride levels to prescribe this? Is the pancreatitis outcome really important for them, more so than you, or less so than you, or the same? Like, how do you think about kind of the broad use in terms of pancreatitis prevention versus just triglyceride declines themselves? Hey, I mean, you're right. Sometimes patients will have one episode of pancreatitis. They will become so sick that they will take care of themselves and not have it happen again, except if they have a genetic problem. You know, taking care of yourself is very hard. It's sort of like, you know, weight loss and diet and whatnot, and it also totally changes the way people live. I actually have a number of genetic LPL-deficient patients who have triglyceride levels that run 400 to 600. They exercise one hour to two hours every single day. They eat zero fat. It is their life. And I have the patients who don't get pancreatitis because of that. What happens in the community? Well, in the community, when people have recurrent pancreatitis, you know, it's expensive, it's a big problem. I think they were right for this drug because it's easy to give. Javier knows I've got patients who I've, you know, tried to solicit the drug kind of out of the usual standards for the trial, because they don't exactly fit for the trial. This is not going to be so hard to take. You know, it used to be, you know, even when GLP-1 drugs came in, people asked the same question: "What will community doctors do?" Here's a drug that you have to give by injection, so they'll get used to using this. I, you know, I think it'll start with big medical centers, then it'll spread out to the community. Doctors adjust. They even learn. Regard to question about inclusion criteria, right, on the SHASTA-4 study. We're working on that right now. The goal is to have enough number of events to show the clinical benefit. I anticipate that effect size will be very large, and I think we have some evidence of that. It would be a balance beteen how severe the patient needs to be and how fast we want to enroll the study, because our ultimate goal is to get to the market as soon as possible, and that's why this program have these two stages: the TG six months with the two studies and then the pancreatitis risk reduction with the SHASTA-4 study up to two years. The final tune of that inclusion criteria, whether it's 1 episode, whether it's two episode, whether it's within the last year, two years or five years, is what we're working now to really assess what is the event rate, what's the sample size, and that will answer that question. Hey, guys. Thanks for taking the question. Ellie, from UBS, thanks for the comprehensive R&D day. Sorry if I missed it, but I just want to clarify on the pulmonary programs, just exactly what data we're getting this year. I know you're adding the FeNO cohorts, the COPD cohorts. Just will we get data from either of those patient cohorts this year? Then I guess just how should we think about what data we will be getting in terms of some of the patient cohorts this year, heading into early next year? And then second part of the question, what you're looking to see. I think you answered it a bit with pheno and asthma, maybe just commenting a little bit more in terms of COPD and what some of the target biology kind of, markers might be there in terms of, MUC5AC. Thanks. With regard to clinical new data before the end of the year, do not expect the FeNO or the COPD. We're working on the protocol amendments now. It takes a couple of months to get that protocol amendment approved, then a few months to get the study done. I would say Q1, probably, of next year, it's likely that we will see the COPD mucus or target engagement data and the FeNO and the RAGE asthma cohort. That expect next year. This year, we're gonna have more normal healthy volunteers and more of the patient cohorts, not the FeNO or not the COPD. You will see more patient data, you won't see these last two cohorts. With regards to the MUC5AC and COPD, you know, I think the number one goal by far there is to look at target engagement. It's the right patient population to do that for the reason that we expressed before. Those are the patients who develop mucus, and they have more production of mucus based on MUC5AC overexpression. I think at this point, that would be the key feature. Now, we're measuring pulmonary function test, exacerbation, quality of life, PROs to assess the level of cough, sputum, expectoration, and all that stuff. It's gonna be, you know, a relatively small study for those type of endpoints, but we're looking at those endpoint in programmatic ways, maybe we do have a surprise there. Patrick at H.C. Wainwright. First, just with PNPLA3, are you going to be looking for a new partner for that program? Secondly, how do you think about pricing and reimbursement in HoFH relative to the biologics, assuming you achieve that target product profile? Regarding ARO-APOC3 with severe high triglyceride, appreciate the opportunity for the early file with the six-month endpoint. I'm just curious, you know, how payers think about that. Would they be looking for some of the maybe longer-term follow-up data? Finally, realizing very, very ahead here, looking at revenues further out, but with the longer-term strategic plans, can you kind of frame for us what revenue targets might look like over the longer term? I'll take the first and the last, and then Tracie can take the middle part. PNPLA3, we think it's a great target, and so we are not looking to partner that at this point. The final question, we are not prepared to give any sort of revenue guidance at this point. I'm trying to remember the two middle ones. I think the first was HoFH and pricing. We have not set pricing for that yet, but it's an ultra-orphan indication, so, you know, you can assume it'll be somewhere between zero and that. What was the other question about? Six months. How would payers react? You know, we anticipate that currently, all payers, the data that they have right now and that we expect they'll have is strictly limited to lowering triglyceride levels. Will they wait for a clinical outcome associated with that, like they did with PCSK9 inhibitors with CVOT studies? I don't know. We're not aware of any trials like we're planning for other drugs. I think we'll be able to satisfy payers quickly in terms of what's the clinical benefit of lowering those triglycerides. Just in term of the sequence of events that will happen with the SHASTA program. One study is three times bigger than the other one. We expect to have fully enrolled the severe pancreatitis study by the time we're filing, you have about nine months or a year to get approved. I expect that soon after the approval, we will have that pancreatitis data, and of course, we're gonna do a supplemental NDA. In the meantime, that can go into the dossier and be part of our value proposition to payers well, right? Great. Thank you. Great. Thanks so much, Luca, RBC Capital Markets here. Maybe Chris, on DUX4, can you just expand a little bit more on what's go, no-go decision here to either file a CTA versus partnering, and maybe what gives you confidence that you can make that call one way or the other within the next 30 days? Then maybe for ANGPTL3, Dr. Goldberg, I know, Javier already touched upon this, but obviously, Ionis and Pfizer had an antisense oligonucleotide going after ANGPTL3. Those ultimately discontinued, giving an actually, cause those depending hepatic fat accumulation and ALT elevation. What's the ongoing hypothesis for what drove that signal, and what gives you confidence that you're actually, that signal was off target and not on target? Maybe last one, going back to crossing the blood-brain barrier, maybe either James or Christy, can you just talk about how you're crossing the blood-brain barrier? We've seen a few others using the transferrin receptors, but some of these companies are now running into anemia signals, wondering if you can comment on whether it's the same approach that you're using or you're using a different approach. Thanks so much. All right, I'll start with DUX4. So we're in a good spot with DUX4. You know, we've done acute tox, we've done chronic tox. The CTA is written. We just need it to press send, and we're happy to do it. You know, we think it's a compelling drug candidate. We think the market's clear. We think the target is clear, so we're happy to do it. As I said in the conference call, we were prepared to do that, I guess, in early April, thereabout, and then we got some inbound interest. And so we just wanted to let that play out. And I think we'll know over the next 30 days or so, which way we're gonna go. About the liver fat. ApoC-III deficiency or any of those treatments is not associated with liver fat, right? The ANGPTL3 issue is, you know, the patients were initially described in St. Louis as being different from all the other patients who have low cholesterol. ANGPTL3 deficiency in humans causes really low levels of cholesterol, triglyceride, HDL, everything, and were described as being different from the patients who are missing, like, ApoB or the MTP protein because they did not have fatty liver. You know, so that you would inhibit the protein and have something totally different from what happens in humans, you know, suggests it's a, you know, it's most likely an off-target effect. I can cover the last question. Yeah, I think all I can say at this point is we use a ligand-targeted approach, and we're not ready to disclose the ligand at this point. All right. I think that's all we have time for today. Thanks, everybody. We appreciate you coming out here today. Thank you.