Ladies and gentlemen, welcome to the Arrowhead Pharmaceuticals conference call. Throughout today's recorded presentation, all participants will be in a listen-only mode. After the presentation, there will be an opportunity to ask questions. I will now hand the conference call over to Vince Anzalone, Vice President of Investor Relations for Arrowhead. Please go ahead, Vince. Thanks, Jonathan. Good afternoon, everyone. Thank you for joining us today to discuss Arrowhead's results for its fiscal 2021 first quarter ended December 31st, 2020. With us today from management, our President and CEO, Dr. Christopher Anzalone, who will provide an overview of the quarter, Dr. James Hamilton, our Senior Vice President of Discovery and Translational Medicine, who has graciously agreed to sub in for Dr. Javier San Martin while he is out ill today, and Ken Myszkowski, our Chief Financial Officer, who will give a review of the financials. In addition, James Hassard, our Chief Commercial Officer, will be available during the Q&A portion of today's call. Before we begin, I would like to remind you that comments made during today's call contain certain forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. All statements other than statements of historical fact, including without limitation those with respect to Arrowhead's goals, plans, and strategies, are forward-looking statements. These include statements regarding our expectations around the development, safety, and efficacy of our drug candidates, projected cash runway, and expected future development and commercialization activities. These statements represent management's current expectations and are subject to numerous risks and uncertainties that could cause actual results to differ materially from those expressed in any forward-looking statements. For further details concerning these risks and uncertainties, please refer to our SEC filings, including our most recent annual report on Form 10-K and subsequent quarterly reports on Form 10-Q. Arrowhead disclaims any intent and undertakes no duty to update any of the forward-looking statements discussed on today's call. With that said, I'd like to turn the call over to Chris Anzalone, President and CEO of the company. Chris? Thanks, Vince. Good afternoon, everyone, and thank you for joining us today. The last quarter was an important period for us and our shareholders because we demonstrated clear advances in multiple development programs that we believe represent key value drivers for their respective product candidates and our proprietary TRiM platform. We see this as positioning us well to build substantial value throughout 2021. We seek to create value in two primary ways. First, we push RNAi and our platform forward to address new diseases, therapeutic areas, and organ systems. This is fundamentally difficult and uncertain because it relies on innovation. Second, we drive our existing pipeline into later-stage clinical studies toward eventual commercialization. This can be more straightforward and, we believe, increasingly predictable as we generate large amounts of data regarding how well the TRiM platform works. We would expect the progress in either of these areas would drive value for us, but our goal is to show measurable progress in both. As we look at 2021, we expect substantial progress on both fronts, with several opportunities in the first half of the calendar year alone. For instance, by the middle of the year, we could have clinical proof of concept for our ability to bring RNAi outside the liver, opening a whole new range of addressable diseases without adequate treatments. We also expect to begin three large phase II -B studies and a phase III study during this timeframe, and we may also have a better idea about how we indicate it, may be able to streamline the ARO-AAT clinical program to accelerate that drug candidate to market. Let's begin by looking at our earlier-stage programs. The power of Arrowhead's TRiM platform is our ability to rapidly discover and develop multiple new drugs targeting diverse disease areas in a way that has been predictable, reproducible, and with an attractive safety profile. Each new program builds upon prior programs, which could make them progressively lower risk. We've seen this in our liver-targeted programs and are applying this concept to our extrahepatic initiatives. We hope to do in many other tissues what we have done in the liver. Given our clinical experience in hepatocyte-targeted programs, specifically in HBV, AAT, APOC3, ANGPTL3, and Lp(a), we generally expect future hepatocyte-directed candidates, such as ARO-HSD and others, to also be highly potent and well-tolerated. Now imagine leveraging that not only in a single new cell type, but with many new cell types. As we have said in the past, we expect to be able to target a new cell type every 18 to 24 months. If we can pull this off, we would expect it to provide a huge amount of leverage in value creation. This is exciting, and it's one reason I believe that the progress we've made over the recent time periods could be just a prelude to something bigger. We think we are now on the cusp of having clinical data to assess the ability of TRiM to knock down target genes in the lung and in solid tumors, and are working toward bringing our first muscle-targeted program into the clinic late this summer. What will success look like for these new programs, and what have we seen so far? First and foremost, we need to have an acceptable safety profile. The TRiM platform for liver delivery has been administered in literally thousands of patients, so we have a good idea about how that performs. While the new tissue types are built on the same idea and same fundamental platform, they are structurally distinct. First, we need to establish that these new molecules are well-tolerated before we can take a breath and exhale, and then focus on assessing efficacy in humans. We think we are almost at that exhale stage now. The studies are still ongoing and data collection continues, but so far, we have not seen anything concerning on the safety and tolerability front for ARO-ENaC, which is our first lung-targeted program, or for ARO-HIF2, our first tumor-targeted program. We still have not seen activity data from either program, but expect to start to see data in coming months. We hope to share some early data by the middle of the year for both programs. Regarding ARO-ENaC, we hope to have preliminary FEV1 data in patients from the first one or two dose levels and also have some ENaC knockdown data in healthy volunteers via bronchial brushing and lavage. While longer-term, we are, of course, focused on the functional improvements in patients, the healthy volunteer data at this point may be more informative. Given the small number of patients we will be treating in the current study, only four per cohort on active drug, it may be difficult to discern FEV1 changes. However, ENaC knockdown in healthy volunteers should be much easier to interpret. Therefore, this is our primary focus right now. Should this be positive, it would represent a huge leap forward for our company and for the entire RNAi field. We believe it would suggest we may not only have a drug in ARO-ENaC, but we may also have a lung franchise that could be leveraged against many gene targets for many different diseases. This would indeed be a big event. Regarding ARO-HIF2, we hope to have some preliminary knockdown data to share by the middle of the calendar year. We're taking biopsies from metastases pre-treatment and during treatment, and we'll be assessing HIF2α knockdown. This is too small a study and too short an observation period to be focused on progression-free survival, but we think if we are able to show good reduction in HIF2α expression in these metastases, we will have demonstrated something truly important. HIF2α is a well-validated target, particularly for the clear cell form of renal cell carcinoma, demonstrating the consistent reduction in expression could be strong evidence that we have a drug. Further, and potentially more importantly, we believe it could also suggest that we have a solid tumor franchise. Our targeting strategy is not designed to be RCC-specific, but rather to enable delivery to a variety of solid tumor types. If we can show reduction of any gene product inside of solid tumors, in this case HIF2α, it would suggest to us that we can address a wide variety of cancer targets across different solid tumors. As with clinical proof of concept in the lung, this would be a giant leap forward and could represent a substantial value inflection point. By the end of the second calendar quarter, we could have proof of concept that we can silence gene expression with RNAi in three different cell types across eight different clinical programs. I don't believe there is another company on the planet that can say that. Later in the summer, we expect to increase our reach to a fourth cell type when we expect to file a CTA for our first skeletal muscle-targeted program. While we're conducting these clinical studies, we continue to work in parallel on multiple additional targets in tumor and pulmonary. For the latter, we have a number of early programs in development, and I expect us to file at least 2 pulmonary CTAs in calendar 2021. We also continue work on our COVID-19 program. We are focused on developing an antiviral approach and are interrogating a number of different RNAi triggers targeting different positions within the current virus and potentially other coronaviruses as well. While we are excited about the various vaccines, mutations in the current virus and preparation for the next coronavirus suggest to us that our work continues to be important. In addition, we are now starting to see promising early results on pulmonary formulation work that may open up some important new possibilities. Specifically, we've been evaluating the possibility of using an inhaler device as opposed to a nebulized formulation for some indications. That would improve convenience and could make for a more viable commercial product for higher prevalence diseases with large patient populations. Our plan for ARO-Lung2, which is in development to treat COPD, was to begin the clinical program with a nebulized formulation and then to work out the necessary technology to switch over to an inhaler. We have decided to hold off on the CTA for now, since we are increasingly encouraged by our new possibilities. We don't think this slows the program's time to market, and in the end may actually shave some time off overall development if the inhaler formulation work enables a more direct path. The ultimate goal is to take forward a therapeutic with optimal efficacy, safety, and convenience in a form that is useful to physicians and their patients. We will provide an update over the next quarter pending completion of a few ongoing studies. Let's now shift to our later-stage programs and discuss our progress toward commercialization. Last quarter, we presented positive data from our ARO-AAT, ARO-APOC3, and ARO-ANG3 programs. We are very encouraged by the results and believe they support rapid advancement of these programs. Specifically, we presented Phase II data at AASLD on ARO-AAT, showing strong reductions in the production of the mutant Z-AAT protein and improvements in multiple biomarkers of alpha-1 liver disease. This was exciting for us, for the alpha-1 field, and for our partner, Takeda. These data were from biopsies after only six months of treatment. We also expect to have 12-month biopsy data over the next month or two. We plan on discussing those data with the FDA and proposing some changes to the study design and endpoints, with a goal of shortening the time to a potential NDA. For ARO-APOC3 and ARO-ANG3, we presented new data on phase I/II studies at multiple medical meetings, including the European Society of Cardiology and the American Heart Association meetings, and subsequently hosted KOL webinars to discuss the data and our plans for their future development. These plans have continued to progress, and we are now preparing to begin the next stages of development. In fact, we have already filed an IND for ARO-ANG3 and intend to proceed with a phase II-B study pending FDA review. ARO-AAT, ARO-APOC3, and ARO-ANG3 are all getting to points where the regulatory and development path and potential timelines become clearer. This, I believe, is a key event. For all three programs, the data generated to date have suggested that the drugs are doing what they are designed to do. There is also a clear need in each disease for new therapeutics. With increased regulatory clarity, we may soon have a direct line of sight for the timelines required to have multiple potential commercial products, as long as the data continue to support advancement and we continue to execute efficiently. We have a high level of confidence about both. In the first half of the year, we expect the following. One, pending FDA review, we intend to begin a phase II-B dose-finding clinical study of ARO-ANG3. Two, file an IND for ARO-APOC3 and then later, following FDA review, begin two phase II-B studies and potentially a phase III study in patients with familial chylomicronemia syndrome. Three, engage with FDA on design, endpoints, size, and duration of treatment for a potentially streamlined ARO-AAT study. Four, potentially report on 12-month biopsy results from the 2002 open label study of ARO-AAT. By the middle of the year, we plan to be on track to share preliminary data for ARO-HSD in healthy volunteers and in patients with NASH and suspected NASH. We expect to be the first company to have clinical data using any modality against the target HSD17B13. The genetic validation is strong for inhibiting the target, and there is clearly substantial unmet need in NASH, so we are eager to see these data and evaluate the next steps for this program. Silencing HSD is thought to confer a possible protective effect against liver disease. Given the biology of this target, we would not expect a decrease in liver fat. Therefore, what we are looking for is simply depth and duration of knockdown. We expect ARO-HSD to be a potent drug candidate, as has been the case for our other hepatocyte-targeted drug candidates. In the second half of the year, we expect the following. One, collect and potentially report on 18-month biopsies from a 2002 open-label study of ARO-AAT. Two, potentially begin phase II-B studies for ARO-ENaC, ARO-HIF2, and ARO-HSD. Three, begin a number of smaller phase II-B studies for ARO-ANG3 and ARO-APOC3 that will run in parallel with the studies that I've already described. There are a number of questions that we would like to answer in both programs that we could address in short and open-label studies. We expect regular data readouts for these programs while the longer blinded studies are ongoing. With that overview, I'd now like to turn the call over to Dr. James Hamilton. James? Thank you, Chris, and good afternoon, everyone. Since we plan to have preliminary data this year for ARO-ENaC, ARO-HIF2, and ARO-HSD, I would like to go through the general designs for those clinical studies and provide an update on their status. First, I will discuss ARO-ENaC, our inhaled RNAi therapeutic candidate designed to target the epithelial sodium channel to treat cystic fibrosis or CF. CF is a rare disease caused by a genetic mutation that leads to mucus buildup in the lungs. It is characterized by airway dehydration and reduced mucociliary transport. Patients with CF can have difficulty breathing and experience frequent and persistent lung infections. ARO-ENaC is in a phase I/II dose-escalating study to evaluate the safety, tolerability, and pharmacokinetic effects of ARO-ENaC in up to 24 normal healthy volunteers, and to evaluate the safety, tolerability, and efficacy in up to 24 patients with CF. The patient portion of the study includes three cohorts, two with six patients each and one with 12 patients. This was the initially planned design. We intend to make protocol changes shortly that will add an additional 12 healthy volunteers who will undergo bronchoscopy with bronchial brushings and bronchoalveolar lavage, or BAL, to evaluate ENaC knockdown in the lung. We are also considering expanding the CF patient cohorts as well. We've completed dosing in all initially planned single-dose healthy volunteer cohorts, and we have been pleased with the safety and tolerability results to date. We believe this is an important finding for ARO-ENaC and for the pulmonary TRiM platform as we begin to expand our pipeline into additional diseases in the lung. This is particularly relevant to drugs inhibiting ENaC, as many of the small molecule ENaC inhibitors have been dose limited by toxicity. We are now dosing CF patients in the first cohort, which we expect to be fully enrolled before the end of next month, at which time we plan to begin enrolling the second patient cohort. What data do we expect from this study? First and most importantly, we are assessing safety and tolerability in all cohorts. In the expanded healthy volunteer cohort, as I mentioned, we will be conducting bronchial brushings and BAL. This method may give us a signal on target engagement and a better understanding of pharmacologic activity. Remember that ENaC is not secreted, we are not able to measure target engagement in the blood, as we are typically able to do for our liver-targeted programs. In addition, in CF patients, we will be measuring changes in FEV1 and in lung clearance index or LCI. These would be indications of functional improvements in mucociliary clearance and lung function. There's clearly a lot of data coming out of this first-in-human study. We are eager to see the ARO-ENaC results. The next program I'd like to highlight is ARO-HIF2. ARO-HIF2 is designed to treat clear cell renal cell carcinoma or RCC. We are currently dosing RCC patients in a phase I-B dose-finding clinical study in three cohorts of at least six patients each, for a total of 18 patients with advanced clear cell RCC. The study is designed to evaluate the safety of ARO-HIF2 and to determine the recommended phase II dose. We are also assessing pharmacokinetics and preliminary efficacy based on RECIST, as well as post-dose tumoral expression of HIF2α and HIF-associated genes. We are dosing the second cohort at this time, which we expect to be fully enrolled this month. The patients in this study are heavily pretreated and have failed multiple lines of therapies. A positive result for this first-in-human study would include data suggesting delivery to tumors, as well as measurable levels of HIF2 knockdown. Similar to ARO-ENaC, we are also looking to characterize safety and tolerability and to select a dose for further studies in phase II. The last program I'd like to describe is ARO-HSD, our investigational candidate for the potential treatment of alcohol and non-alcohol related liver disease. There is strong genetic data supporting HSD17B13 as a target for NASH and alcoholic liver disease. We are conducting a Phase I/II single and multiple dose escalating study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of ARO-HSD in normal healthy volunteers, as well as in patients with NASH or suspected NASH. We have completed the single-dose portion of the study in healthy volunteers. We are currently enrolling and dosing the multiple-dose patient portion of the study in NASH or suspected NASH patients. We have completed the first patient cohort and expect to complete enrollment of the second patient cohort this month. After that is complete, there are two more patient cohorts to enroll sequentially. This target is also not secreted. In order to assess target engagement, we utilize liver biopsies. It's important to mention that this study only involves two doses, which relative to other later-stage NASH studies is only a short duration of exposure. We don't expect to see substantial signs of disease improvement, but rather we are focused on selecting the dose level and regimen achieving optimal gene target silencing. However, we know the platform is highly effective at silencing hepatocyte-expressed genes, so we would expect a high level of target engagement. In addition, we are the first to study inhibition of this target in humans, so we will see if there are any early encouraging signs of efficacy, even though this would be unexpected. As mentioned earlier, we expect all three of these programs to have preliminary data readouts around the middle of the year. It's too early to know in which order they will come, but we expect this to be an exciting period with all these potential data reports coalescing roughly around the same time. Our intention would be to report top-line data highlights in a press release and then further present a fuller data set at an appropriate medical meeting. I will now turn the call over to Ken Myszkowski, Arrowhead's Chief Financial Officer. Ken? Thank you, James, and good afternoon, everyone. As we reported today, our net loss for the quarter ended December 31st, 2020, was $20.7 million or $0.20 per share based on 102.8 million fully diluted weighted average shares outstanding. This compares with a net loss of $2.7 million or $0.03 per share based on 97.1 million fully diluted weighted average shares outstanding for the quarter ended December 31st, 2019. Revenue for the quarter ended December 31st, 2020, was $21.3 million compared to $29.5 million for the quarter ended December 31st, 2019. Revenue in both periods relates to the recognition of a portion of the upfront payments and milestones received from our license and collaboration agreements with Janssen. Revenue in the current period also includes the recognition of a portion of the $300 million upfront payment due upon the signing of the collaboration agreement with Takeda. This payment was received in January. Revenue for the Janssen and Takeda agreements will be recognized as we continue to work toward completing our performance obligations of managing the clinical trials in process and certain manufacturing-related services. We anticipate the remaining deferred revenue of $6.7 million associated with the Janssen collaboration will be recognized in the next fiscal quarter. The remaining $292 million of revenue associated with the Takeda collaboration is anticipated to be recognized over approximately two years. Any additional milestones achieved with our collaboration partners would be additive to this projection. Total operating expenses for the quarter ended December 31st, 2020, were $45.4 million compared to $34.3 million for the quarter ended December 31st, 2019. This increase is primarily due to increased personnel cost and non-cash stock compensation in R&D as our headcount continues to grow. The increase is also due to increased candidate-specific and discovery R&D costs. Net cash used in operating activities during the quarter ended December 31st, 2020 was $38.9 million, compared with net cash used in operating activities of $23.5 million during the quarter ended December 31st, 2019. The key driver of this change was the increased R&D cost discussed. We continue to estimate our full year cash burn to be between $200 million and $250 million. Turning to our balance sheet, our cash and investments totaled $416.2 million as of December 31st, 2020, compared with $453 million at September 30th, 2020. The decrease in our cash and investments is primarily due to cash used for operating activities. With the collection of the $300 million upfront payment in January 2021, our current cash and investments total approximately $700 million. Our common shares outstanding at December 31st, 2020 were $103.2 million. With that brief overview, I will now turn the call back to Chris. Thanks, Ken. We have a lot in front of us this year. We expect waves of clinical data readouts throughout the year from ARO-HSD, ARO-ENaC, ARO-HIF2, ARO-APOC3, ARO-ANG3, and ARO-AAT. We expect to gain clarity on potentially streamlining and accelerating the ARO-AAT development program. We expect to initiate multiple phase II-B studies for ARO-HSD, ARO-APOC3, and ARO-ANG3, and possibly for ARO-ENaC and ARO-HIF2. We also expect to initiate a phase III study for ARO-APOC3 in FCS patients. We expect to file at least three new CTAs this year, including our first for a candidate targeting skeletal muscle. By the end of the year, I expect Arrowhead to have at least 11 clinical programs targeting four different cell types, and eight of those clinical programs could be wholly owned. This is indeed a substantial amount of potential value creation. We feel great about where Arrowhead is today, and we're confident about what we can accomplish going forward. It seems like all the pieces are in place for scalable and sustainable growth. We have a strong balance sheet and are disciplined in our use of cash, which allows us to move forward rapidly in a capital-efficient manner. We also are eligible for substantial non-dilutive capital in the form of milestone payments from Amgen, Janssen, and Takeda as our partner programs continue to advance. Ultimately, if any of the products are commercialized, we will be eligible for royalties on sales. We have an increasingly validated technology platform in TRiM, and we believe TRiM is on the verge of potentially showing that RNAi can be a powerful therapeutic mechanism for diseases throughout the body. We have a large and rapidly growing pipeline of differentiated product candidates addressing diseases without adequate treatment options. These are all innovative first-in-class molecules, not fast follower, incremental, or me-too products. Lastly, we have the right team in place and an unwavering culture of challenging the norms of drug development. Arrowhead always finds a way to be better, faster, and more efficient than others in the field. This is a powerful combination, and it gives us the opportunity to make a difference in the way numerous diseases are treated. Thanks again for joining us today. I would now like to open the call to your questions. Operator? Our first question comes from the line of Salveen Richter from Goldman Sachs Group, Inc. Your question please. Good afternoon. Thanks for taking my questions. Just one on the ENaC program. Could you help us understand the threshold knockdown that you want to see here and what you saw pre-clinically that could translate? On the HIF2 program, what gives you confidence or optimism with regard to the translation in man? Thank you. Hey, Salveen. Thanks very much. Let me start with ENaC. That's a tricky question. There's good experimental evidence, there's good genetic evidence on the possibility of knocking down ENaC and helping that mucociliary clearance in these types of patients. The fact of the matter is no one's been able to create a therapeutic that can do that safely, we are true pioneers here. It's hard to say what sort of knockdown could be helpful. The best idea we've got, I suppose, is if you look at the genetic analysis, essentially heterozygous ENaC knockouts in humans do see a clinical benefit, we think. It feels like if we can reach 50% or so knockdown, we could see something helpful. There's an awful lot of green between where we are and the pocket, as they say in billiards, and so we still have a lot to learn, but that sort of feels like the bogey to us right now is 50% knockdown could be helpful. With respect to HIF2α, that's also a hard one. We have done as much as we've been able to do in animal models. But as you know, translation is always a trick with oncology, and so we're just waiting to see. We're looking forward to seeing the data over the next couple of months, and we'll see where we are. The animal data have been good. We feel confident that we'll see knockdown. We don't have a good idea about how much knockdown you really need to see to see a clinical benefit. Similar here, I think we would call a win 50% or so knockdown. That's a bit arbitrary, but that feels reasonable to us, and so we'll see how we stack up against that over the next few months. Thank you. Sure. Thank you. Our next question comes from the line of Maury Raycroft from Jefferies. Your question please. Hi, everyone. Thanks for taking my questions. I just wanted to do a quick check on timing for the three phase I readouts. It sounds like you can't predict the order of the readouts, but Chris, I think you mentioned by end of 2Q in your prepared remarks, so just checking if the guidance is for end of 2Q or is it softer and a possible update could come in 3Q. No, we're shooting for the end of the second quarter. These are ongoing studies. Nothing's going to be finished by then. We'll see what we have in hand, and we'll see if we have interpretable data. That's going to really be the kicker for us. I think that we can hit that by the end of the second quarter. That's our goal. Got it. Okay. You'll report the data by the end of the second quarter then. That's the goal. Yes. Again, it's going to be a subset of data. It'll be just top line. As James mentioned in the prepared remarks, our goal here is to show a fuller data set at appropriate medical meetings. Our goal here is to give you a taste, to show you whether or not it appears the drugs are working. We'll disclose more going forward. Got it. Okay. For the ENaC data, can you clarify how many subjects you plan on reporting there and with the additional 12 subjects that you're planning on enrolling, do you have an idea of what the doses and dose range will be? Let's see if we can unpack that. I can't tell you how many patients we're going to be reporting on because I just don't know. As I said, I think we'll be talking about this sort of midstream, but my hope is that we'll have some data from the first or, and maybe the second dose cohort in the patient population with respect to the healthy volunteers and the bronchial brushing and lavage. James, you want to address what those doses are? Yeah, sure. That dose is actually up to us to select based on what we see in the previous cohorts, in the healthy volunteer cohorts. It's likely that since the safety profile has been favorable, we'll go with the highest dose cohort to give us the best chance of showing knockdown either in bronchial brushings or BAL. Okay. Fair enough. Last quick question, just for the HIF2 patients, can you say how many biopsies you have already and maybe give a sense of what baseline HIF2 expression levels look like? We haven't seen the data yet. These are going to be batched. We haven't seen any data yet. James, you want to talk about how many biopsies we've had so far? Yeah, sure. We've completed pre- and post-dose biopsies in all six of the cohort one patients. Pre-dose in five of the cohort two patients. Now we won't know about viability of those until we start staining the slides. How many of those we'll be able to analyze, we don't know that yet, but that's how many biopsies have been completed. Got it. Okay. Thank you very much for taking my questions. You're welcome. Thank you. Our next question comes on the line, Shawn Egan from Citi. Your question please. Hi, guys. Thank you for the comprehensive update. Are you able to provide any more details on the safety update you provided today for ENaC? Just how many patients? Is it just healthy volunteers, or are there actually CF patients in there as well? I have one follow-up on the skeletal muscle program. Sorry, you broke up there a little bit. You're asking how many patients have been treated so far with ENaC between healthy volunteers and patients? Was that the question? Just the safety update you gave today that everything looks good so far. How many patients does that include? Sure. That includes all the healthy volunteers and the first four patients in the study. That's all four. Sure. You want to go into how many healthy volunteers that is? Yeah, sure. That's a total of 24 healthy volunteers, six per cohort, and then we'll add that additional 12 for the BAL studies. Great. Thank you. For the skeletal muscle, it seems like it's an active area for RNAi and antisense oligo. Are the gating steps for that program, is it compound optimization at this point, or is it more about being strategic for the indication that you're going after? For this first one, we're just on the conveyor belt now. Once you have nominations and such, there's just sort of a time it takes to get through GLP tox and the like, and we're just in that right now. We feel comfortable that we've got drug candidates. We just need to complete the IND enabling steps, and we are in that process right now. We feel comfortable that we're on track to file that CTA sometime in the summer. Okay. Thank you so much. Appreciate it. You're welcome. Thank you. Our next question comes from the line of Luca Issi from RBC Capital. Your question, please. Terrific. Thanks so much for taking the question and congrats on the progress. One on ARO-AAT. I think you mentioned optionality to streamline the SEQUOIA trial and the upcoming FDA meeting. Can you just give us a sense of what's on the agenda for that meeting and what are some of the key goals that you're hoping to achieve during that meeting? That's one. The second on HIF2α, maybe bigger picture. Can you expand a little bit more on what's the bogey for success here? I understand that this is a trial, primarily dose escalation, and you're looking at PKs. What are some of the key biomarkers that you're really focused on to know whether this is a molecule that is worth further pursuing? Thank you. Sure. First, with AAT, I can't go into that too much because we really haven't started discussions with the FDA yet. We're still collecting some data. We want to collect the 12-month paired biopsy data and then go to the FDA and have an open discussion about how we may be able to change endpoints. Certainly, we will want to change the length of the study because what we think we've learned is that we see a pretty substantial effect much earlier than we expected. As you may recall, we were first planning on treating patients for at least two years. That does not appear to be required at this point, we'll shorten the study. We also want to see if we can agree on some maybe more appropriate endpoints. Let us have those discussions, and then we'll get back to you on what the FDA has advised. With regard to HIF2α, I tell you, since this is our first solid tumor targeting program, our primary focus here is just two things, safety and tolerability, of course, and so far that's been acceptable. Second, knockdown. As I mentioned there, we just haven't seen data yet. Those biopsies are going to be batched, and we'll have an idea over the next several months what kind of knockdown we get. We're really focused on knockdown not only for the drug for ARO-HIF2, but also for the franchise if we see that we are getting consistent and good knockdown. What does good mean is hard to say, but it sort of feels like if we are in the 50% or so knockdown range, we feel pretty good about that. If we can hit that, we think we've got a drug, and we think we've got a franchise. HIF2α, as you know, is a well-validated target. There's another drug right now in development that looks quite good. We think that as long as we can show reasonable knockdown, there's a place for us with this drug. Again, we see a lot of upside if we can knock down HIF2α in solid tumors. We can knock down, we think, a whole host of other cancer targets, fill in the blank. There's a number of targets that we're going to want to go after, maybe ourselves, maybe in partnership with others against various tumors. We're in a really interesting, really exciting spot right now where we're just waiting for data, and if those data look positive, then I think we're off to the races. Very helpful. Thank you. You're welcome. Thank you. Our next question comes from the line of Esther Rajavelu from UBS. Your question please. Hey, thanks, Chris and team. I have a couple on ARO-APOC3 and then one on ARO-AAT. In the past, you've talked about initiating a phase III registrational trial in FCS, and your comments today seem to suggest that that's a potential. Am I reading too much into it, or are you still sort of going strong with the FCS? With regards to the two phase II trials that you're going to start in patients with, I believe what you said in the past was severe hypertriglyceridemia and those with levels greater than 150. I noticed that the trial in the severe phase II patients, you're excluding patients who have recent pancreatitis. Why is that? That's two questions in there. Sure. With respect to FCS, yes, you are reading too much into that. We are going full speed ahead on a pivotal study in those patients. Our timing of this is we plan to file an IND for ARO-APOC3 first and then follow that up with plans for that pivotal study. It is still our intention to move forward as quickly as we can on that population. We think it's a strong unmet medical need. We think that ARO-APOC3 is going to be a really important drug for those patients, we are full speed ahead there. With respect to ARO-APOC3, I'll just say a couple of things then I'll hand it over to James. The two phase II-B studies, as you know, are going to be in patients with severe hypertriglyceridemia, so those patients above 500. We view that as kind of our fat market, right? We think it's a grossly underserved market. The regulatory pathway there, we think is reasonably clear. We think it's a pretty large population. It's one that we're really focused on. We also want to look at, in the phase II-B study, those patients who have elevated triglycerides. Say between 150 and 499. We think that that is also an unmet medical need that we think would require a more comprehensive phase III study, probably an outcome study. I don't know that we're going to do that, but we want to retain the optionality. We want to do that phase II-B study right now, just in case in the future, we're going to want to expand into that patient population. With that, I'll hand it over to James. Sure. The question was about excluding patients with pancreatitis in the ARO-APOC3, is that right? Yeah, that's right. Yeah. We actually don't exclude patients with pancreatitis in either of those phase II-B studies in either the severe hypertriglyceridemic or the kind of middle-of-the-road greater than 150 high triglycerides study. We do have an exclusion for any patients with active pancreatitis. Within the last 12 weeks. We just don't want anyone in the study who has recently had pancreatitis and may still be suffering from associated sequelae. We actually have some endpoints in the severe hypertriglyceridemic study looking at rates of pancreatitis and things like that. We don't exclude those patients. Got it. It's only if they've had it within the last 12 weeks or so that you're not going to include them. Right. Prior to their first dose. Excluding patients who have very recently had pancreatitis. On AAT, you have a few readouts in 2021. Can you frame for us some of the scenarios for that 12-month readout and what the read-through could be for the phase III trial? It sounds like in your response to a prior question, you seem to have more confidence, Chris, that you may not meet that 2-point reduction in fibrosis score for registration. How are you thinking about it? Are you going for that polymer reduction rate and maybe tying that to other studies that have shown a link between polymer reduction and fibrosis? Yeah. Again, I don't want to speak too much on this because I don't want to get out ahead of our discussions with the FDA. In a nutshell, yes. I think that it's clear that the accumulation of the Z protein is what causes alpha-1 liver disease. I think it's clear as day. We think that we can make an argument that that could be an approval endpoint or at least part of a composite endpoint, that we shouldn't have to show a reduction in fibrosis. If that's not an approval endpoint for NASH, we don't think that should be an approval endpoint for this kind of rare disease. Frankly, the SEQUOIA study wasn't dependent upon resolution of fibrosis either. It was improvement in a histologic grading scale without worsening of fibrosis. Our hope is that we can move that a bit as well because again, we think that the biology is increasingly clear on these folks, and that simply reducing Z burden could be a good marker. Okay. Thank you. You're welcome. Thank you. Our next question comes from the line of Ted Tenthoff from Piper Sandler. Your question, please. Great. Thanks, guys. Thanks for the update. Kind of changing tack a little bit. Much going on here. You guys have had a lot of success with partnering assets, both hepatitis B and obviously AAT. As we look forward, what is Arrowhead going to be when you grow up? Are you going to be a targeted cardiovascular company? With so much going on in oncology with respect to combos, is that something that might be a partnerable asset? Liver disease, similarly. Give us a broader sense for how you're looking at these different assets and what you think is going to be core in the future. Thanks. Yeah. Thanks, Ted. That's a great question. It's a dynamic question. Yeah what we are capable of focusing on will, of course, change as we grow and such. Yeah. Here's what we see broadly. As you know, Ted, you've followed us for quite some time. Even when we were a $40 million company, we never saw ourselves in the future as a company that focused only on a specific therapeutic area. We just thought this technology was too powerful, and we thought there was too much value to create to focus that narrowly. We've done an awful lot of work over the last decade, and again, you've seen most of that, looking to push this technology into other cell types, and we're now just on the cusp of that. It gets to the question, okay, with this embarrassment of riches that we've talked about a lot, what do we keep in-house and what do we look for partners on? As we've said in the past, at least for right now, cardiovascular and pulmonary make a lot of sense to us. We like the synergy of those two areas. We've got an awful lot to offer those types of physicians. Those will not be the last areas we're going to focus on. That I can virtually guarantee you. As we build up other franchises, I am quite certain that we will build out sales infrastructure and marketing infrastructure in other areas as well. Will that be oncology? It could be. In the near term, though, oncology is hard. My hope is that we see some good positive data in ARO-HIF2 that would enable us to bring in a good partner to start to really blow out that franchise. Yeah. It doesn't mean that we won't have our own wholly owned offerings. At some point, we'd be certainly open to working with a broad-based oncology company with deep expertise to help us prioritize targets and such. We're not there yet. We want to generate some data first, at some point, that probably makes some sense for us. Yep. Perfect. Makes a lot of sense. Yep. Thanks, Ted. Thank you. Our next question comes from the line of Alethia Young from Cantor. Your question, please. Hi, guys. This is Li on for Alethia. Thanks for taking our call. Just wondering if the HIF2 program looks successful, what other targets might be of interest to you in oncology? How are you thinking about the other companies with similar NASH targets? Thank you. Sorry. The question was other oncology targets? Yes How do we fit? Okay. The other one was how do we fit with other NASH strategies? Is that where we're going? Yep. Okay. Yeah, I don't have much to tell you on the oncology targets. We are working with some other targets. We haven't disclosed anything there, but we do have some internal programs. As I mentioned just a second ago, we would like to bring in a partner at some point. I don't know when the right time is. I don't know if it's this year or next year or some other time. To the extent that we have positive data, we'd like to do at least part of oncology with a partner. I don't have much to offer on other targets we're thinking about right now. With respect to NASH, boy, NASH is hard. We like the genetic data for HSD. It is compelling that if you can knock down HSD, it does seem to have a bit of a protective effect against NASH. Doesn't mean that should be a silver bullet. In fact, I would expect that NASH is going to be more like HBV in that it's going to be a combination approach. I have no idea what the right combination is, and frankly, it's probably a different combination for different patient populations. I think we're learning that it's probably a number of different diseases. We think that HSD could be a really nice backbone and could help a variety of these patient populations, and then you can layer on top of ARO-HSD some other compounds. It's too early for us to tell right now because, again, we haven't even seen any data yet, but that's sort of how we see it. We've also said in the past that we like the idea of HSD for alcoholic hepatitis as well. The genetic data there were at least as exciting as they were for NASH. While we're not doing anything right now in those patient populations, I could foresee us getting into that at some point in the future. Sorry, that's sort of a non-answer answer, but that's how we're thinking about NASH right now. Okay. That's helpful. Thank you. You're welcome. Thank you. Our next question comes from the line of Patrick Trucchio from H.C. Wainwright. Your question, please. Thanks. Good afternoon. I'd like to follow up on the cardiometabolic programs. I'm wondering what questions you're looking to answer in the smaller open label studies with ARO-APOC3 and ARO-ANG3. Secondly, how many studies would you anticipate and how many patients would you anticipate enrolling in these studies? When would the data from these studies be expected? Yeah. Thanks. I'm glad you picked that up. I think it's an important point. We've talked in the past about the two phase II-B studies for APOC3 and the one phase II-B study for ARO-ANG3, and of course, the phase III in APOC3 for FCS patients. We've talked about those a lot. We are now just starting to explore some other questions for these smaller studies. We haven't set on those yet. I assume that by our next conference call, we'll have set those and probably set those in motion a bit, so I can talk about that more then. At this point, we're exploring what those mean. There's going to be a handful of these things. Our goal here was twofold. One is to answer as many questions as we can during this timeframe because, look, these phase II-B studies are going to be blinded, and they're going to be, not long, but say, one year of exposure. There's going to be a timeframe that we can't move into a pivotal study until those are finished. We might as well take advantage of that time to answer some other questions. We're looking to do that. I think these are going to be shorter studies. Many of them or some of them can be open-label, and so it gives us a chance to report on some of these studies while the longer ones are still in process. It allows us to continue to talk about these and tell you about what we're seeing. I really can't give you specifics yet because we're still in the trenches on that. I expect that we'll have those set over the next couple of months or so. Got it. Just a few on the lung programs follow-ups. First on ARO-ENaC, what drove the decision for the protocol changes? Is that something FDA asked for, or what specifically is the driver of those changes? On ARO-COV, a competing RNAi program had been delayed because of the need to conduct more work in a hamster model. I'm wondering how things are progressing for ARO-COV and if this program could begin human trials in 2021. Secondly, to what extent are the new emerging variants impacting this program? Should we expect two or more RNAi triggers to avoid resistance? How do you view RNAi antiviral positioning as compared to the monoclonal antibodies, several of which have the EUA authorizations, Emergency Use Authorizations in the U.S., but they appear to have some resistance issues with these new variants. There's a lot of questions there. Let's start with ENaC. The changes in protocol were driven entirely by our desire to look at knockdown healthy volunteers. It wasn't required by anybody. It wasn't included in the first protocol because frankly, we didn't have an assay yet. We weren't really sure we could measure it. Since then, we have developed this assay, and we're ready to go. Now we want to look at bronchial brushing and bronchial lavage in order to see knockdown in healthy volunteers. That's going to be a really important measure for us because as I mentioned in the prepared remarks, this is a small study in patients. It's going to be difficult to see FEV1 changes in four patients in a given cohort, just because it's too small. This gives us a better measure on how well this drug is working and how well it's delivering to pulmonary epithelial cells. That was the rationale for changing the protocol and including those folks. Now with respect to COVID, we've not been able to move as fast as we wanted to on COVID, in large part because we don't control the animal models, and it's been hard to get slots to do these animal studies. We have not been as fast as we have been in other areas where we can do our own studies or we've got a larger variety of CROs that we can work with. It's lagged a bit because of that. We're still excited about it, of course. You mentioned the new variants that people are talking about. That has not affected our program, but it has just reinforced our belief that there is a real role here for RNAi-mediated antivirals. It is certainly possible that at some point this virus is going to mutate around the vaccines. Our goal here was to make a broad-based antiviral that not only could work against this current coronavirus, but also potentially future coronaviruses. This is sort of playing out the way we thought it might play out, and again, it just underlines the need for our kind of therapeutic. As we've shown with HBV, we know we're pretty good at playing in antivirals. Your point's a good one about multiple triggers. The way we view this is probably multiple triggers is going to be better than a single trigger for the same reason that it was for HBV. As you may remember, our HBV compound has two different triggers. One reason is to guard against mutation. The other reason is to give you broader coverage across genotypes. That'll be the case here as well for the wide variety of coronaviruses that are out there. Got it. That's helpful. Thank you very much. You're welcome. Thank you. Our next question comes in the line of Mayank Mamtani from B. Riley Securities. Your question, please. Hi. Congrats on a productive 2020, it seems like you've got a busier 2021 ahead for you. Thanks for taking my question. A quick follow-up on ENaC. Is there anything you've learned from a PD standpoint or anything from an alternative approach antisense that gives you confidence at this point on target engagement? Anything you can comment on that? Yeah, that's a good question. It's hard for us to interpret the antisense data that we've seen. There's been no bad news there for us, but there's been no good news either, the way we look at it. No, unfortunately. We'll have to wait to see what those data look like, and we're of course anxious to see what our data look like. We're going to know a heck of a lot more over the next couple of months, that's for sure. Okay. Then just a quick follow-up on the biopsy duration for the HSD program and anything, if at all, we learned from the surprise six-month biopsy we got from the AAT program. Is there any read-through, again, I understand it's different proteins we are talking about, different types of knockdown, complicated diseases, any read-through you guys think internally as you think about the NASH program? I don't know that there's read-through. What we've learned in all these programs is that all these proteins are different. All the triggers are different. Depending upon the trigger and the protein knockdown, depth and duration are going to be different. We are confident that we will see good, deep, and durable knockdown in ARO-HSD because of our experience with HBV and AAT and APOC3 and ANG3 and Lp and others. I don't know that we learned anything in particular with AAT that we can apply to HSD. I think success here is pretty narrow. We're just really looking at depth and duration of knockdown. As we mentioned, we're not really looking for alleviation of disease in this very short study. We don't expect it. We're trying to pick a dose. Unfortunately, since we don't know of a circulating biomarker, the only way to choose a dose is to get in there and take a biopsy and see how deep and durable the knockdown is. Then we'll take that into a larger phase II-B study that may give us some idea about disease progression. We don't expect to learn anything about that at this point. To clarify, six-month duration biopsy, right? Or 12 months? We do two different post-dose biopsy time points. One is at day 71 post-dose, and the other is after the last dose. These patients get two doses. The other is at day 169. We staggered them to get a better idea of duration. Okay, great. My final question on, as you think about cash flows, and you obviously have some partners coming in, J&J and Takeda. How should we think about your burn rate for 2021? Also keeping in context some of the near-term- I think we might have lost you. You're very quiet, Mayank. Can you hear me now? Yeah, you're back. Yeah. Final question was on cash flows. As you think about 2021 and think about the different partner milestones from J&J, Amgen and Takeda, how should we think about your burn rate, again, in context of some of the commercial stage programs might be getting pushed out a little bit, like APOC3 and AAT obviously being partnered out? How should we think about the expense for 2021? We reiterated today that we expect to burn between $200 million and $250 million in fiscal 2021. We've got plenty of cash to afford that. I do think that we have a chance of triggering some milestone payments during that time. We can't give you any guidance on any of that, because A, it's uncertain, and B, even if it was certain, I can't tell you until we get it. I think it's possible. Again, worst case is we don't trigger any of those this year. That's okay. We have plenty of cash right now to absorb that kind of burn. Next year, again, I feel quite comfortable that we can have access to additional milestone payments. Look, I feel good about our balance sheet right now. I feel good about our access to additional capital between all three partnerships. Excellent. Thanks for taking my question. You're welcome. Thank you. Our next question comes from the line of Keay Nakae from Chardan. Your question, please. Yeah, thanks. Chris, with respect to if your working thesis right now is that 50% knockdown could have an effect on the disease, should that prove to be too low based on your current dose levels and dose intervals, do you believe you could go higher than that to achieve a higher knockdown if needed? Yeah. We'll see. It'll be really helpful to see what the dose response looks like. If in fact we see 50% knockdown at the highest dose we're giving, at least what we've seen so far, we see no signs that we can't escalate more. It's not a traditional cancer trial, where we dose as high as we can till we get people sick and then we knock the dose down. We don't expect dose-limiting toxicities. To your point, sure, it is certainly possible that we get 50% knockdown and we still think that there's more knockdown to be had. As long as we're not seeing DLTs, we're happy to escalate. Like I said, neither in HIF2α nor in ENaC so far have we seen evidence that we've got a safety issue. Great. Thank you. You're welcome. Thank you. Our next question comes from the line of Mani Foroohar from SVB Leerink. Your question, please. Thanks for taking the question, guys. I want to quickly follow up on something, I think it was Maury actually touched base on this. Around the ENaC readout, you mentioned in your prepared comments it's reasonably possible to see an uninterpretable or unclear FEV benefit while seeing a very substantial knockdown benefit in the healthy normal volunteers. Should you see that data set, which is one that's a profile that we'll see in the early data sets from Vertex, Translate Bio, et cetera, many others. How do you interpret that as either A, the target isn't effective, or B, you need to dose higher? How do you choose to move forward from a data set that doesn't necessarily give you a relationship between knockdown and dose and efficacy? Yeah. Look, it's hard to play that game until we see the data. I guess the broad answer would be, look, if we saw good knockdown, but in those four patients, we can't discern FEV1 changes. I don't think that we're so worried at this point. We say to ourselves, this is good news. We've got a drug that is working the way we want it to. We've got a franchise, certainly, we think that we can go into other disease areas. Now with CF, look, let's treat some more patients because four is not a very large number in a cohort. Let's see if we can start to see an FEV1 change if we get to 10 or so patients. That's one. Second is, look, it's a pretty short study as well, we'd be happy to assume we're getting good knockdown. Maybe we just need a bit more in the way of dosing to start to see those manifest in FEV1 changes. All is not lost if we cannot register an FEV1 change, but we see good knockdown. To the contrary, I think that suggests that we have something that's really powerful. We've got plenty of time this year to treat some more patients, as well as to treat them a bit longer, or at least monitor them longer to see if we can see some FEV1 changes. Great. That's really helpful. The cohorts we'll have middle of the year will be the two lower dose cohorts, so we still have the top dose in CF patients to go. Also, it would be the baseline characteristics of the patients. When you're talking about small Ns like this, that may make a difference. It shouldn't matter theoretically, what the genotype is or background therapy, but this is a small N. I think the main point here is that we get knockdown, we get functional delivery, and we're safe, and that's a win. Right. That's what we want people to focus on. Let's look at FEV1, of course, because that ultimately is going to be important. When we're looking at this drug over the next couple of quarters, what we're really focused on are the knockdown data, and of course, the safety and tolerability of the drug. If both those are positive, we are off to the races. We'll continue to look at patients going forward. That's really helpful. Then hopping over to NASH. There've been a couple of other companies that have also commented on the genetic data. Obviously, there's some evidence, unclear if it's correlative or causative in terms of potential benefit, in both alcoholic and non-alcoholic steatohepatitis. What kind of data sets would you need to see, maybe in later-stage studies from you guys, to parse that out and say, okay, this is really causative, and a knockdown of HSD is going to be reasonably expected to show a benefit in a longer-term pivotal trial? Are there biomarkers you're tracking? Are there early clinical data sets that we might see as early as 2022 to sort of parse out that causation correlation issue? Yeah, sure. I'll take that one. The easy one for this target is ALT, and that's been correlative to the loss-of-function mutation that those individuals tend to have lower ALTs. That's an easy biomarker for us to read out in early-stage studies and beyond. Beyond that, there's not a whole lot else from a biomarker standpoint in terms of imaging or other blood tests. I think then you're looking at phase II-B biopsy studies to show proof of pharmacologic effect and benefit. Great. That's really helpful. Thank you. Thanks for taking my questions. You're welcome. Thank you. This does conclude the question and answer session of today's program. I'd like to hand the program back to Chris Anzalone for any further remarks. Thanks, everyone, for joining us today. It's been a pleasure to speak with you, and we'll talk to you next quarter. Thank you, ladies and gentlemen, for your participation in today's conference. This does conclude the program. You may now disconnect. Good day.