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 over to Vincent Anzalone, Vice President of Investor Relations for Arrowhead. Please go ahead, Vince. Thanks so much. Good afternoon, thank you for joining us today to discuss Arrowhead's results for its fiscal 2023 Q1 ended December thirty-first, 2022. With us today from management, our President and CEO, Dr. Christopher Anzalone, who will provide an overview of the quarter, Dr. Javier San Martin, our Chief Medical Officer, who will provide an update on our mid and later-stage clinical pipeline, Dr. James Hamilton, our Chief of Discovery and Translational Medicine, who will provide an update on our earlier-stage programs, and Ken Myszkowski, our Chief Financial Officer, who will give a review of the financials. In addition, Tracie Oliver, our Chief Commercial Officer, and Patrick O'Brien, our Chief Operating Officer and General Counsel, will be available during the Q&A portion of the 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 are forward-looking statements 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 our quarterly reports on Form 10-Q. 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. Arrowhead currently occupies a unique position within the biopharma world. I believe that RNAi as a modality and our proprietary TRiM platform in particular, are considered increasingly validated. RNAi is a potentially powerful way to treat many disease states. It appears to largely work as intended across numerous clinical studies, has the potential to be highly specific, and has been generally well-tolerated. Overlay on top of this a scarcity premium. There is a clear scarcity of companies capable of developing RNAi therapeutics well, and extreme scarcity of those capable of bringing RNAi outside the liver. These factors combine to position Arrowhead to create substantial value for our shareholders and the patients who rely on us for life-altering new medicines. I think this also frames how we should view Arrowhead currently, the progress we will discuss today, and what these mean for the future. The two primary components of this sort of analysis are the ways in which we are expanding our technological reach and the ways in which we are leveraging our more proven technology. Let's begin with how we are expanding our reach. As you know, our pulmonary franchise is currently comprised of three clinical candidates, ARO-RAGE, ARO-MUC5AC, and ARO-MMP7. With our announcement last week that the ARO-MMP7 Phase 1/2 study initiated, we are now treating subjects in all three programs. We remain on track to begin early data disclosures for ARO-RAGE and ARO-MUC5AC in the Q2. This is an important milestone for us. We view the lungs as a target-rich environment and don't see two or three drugs coming out of that franchise, but rather potentially eight or nine. As with hepatocytes, once we have clinical validation that we are able to address the cell type and reduce expression of a target gene in a well-tolerated fashion, we believe the franchise will be substantially de-risked. At that point, we have an expectation of success for future programs in terms of our ability to safely silence a target gene. As such, clinical proof of concept in the first one or two programs within a cell type has the potential to unlock substantial value. We believe we will be there, we believe we will be there for our pulmonary franchise next quarter. Given what we learned with ARO-ENaC and our non-clinical data using ARO-RAGE, ARO-MUC5AC, and ARO-MMP7 across several animal models, we are optimistic that we will see clinically relevant gene knockdown in a well-tolerated fashion. We have not spoken about our muscle-targeting franchise for some time, and I'm pleased to announce today that we intend to move ARO-DUX4, our candidate designed to treat facioscapulohumeral muscular dystrophy or FSHD, into clinical studies next quarter. This is another example of our drive to apply RNAi to unmet medical needs wherever they are. We have completed a large number of non-clinical studies, including acute and chronic GLP toxicity studies, we look forward to bringing this potentially important medicine to the patients who need it. Another important milestone relating to technology expansion that we expect next quarter is disclosure of the next cell type we'll be targeting and a presentation of our supporting non-clinical data. This and our work in the pulmonary and skeletal muscle spaces represent substantial growth opportunities for the company and would bring RNAi closer to reaching its full promise as a revolutionary therapeutic modality with the potential to address many new diseases. These programs are early, but they are the next great leaps forward for Arrowhead. The second calendar quarter of 2023 is indeed a busy time for demonstrating Arrowhead innovation. Let us now turn to our liver programs. We have demonstrated across multiple candidates in many clinical studies and in thousands of patients that our liver-directed candidates appear to achieve high levels of target engagement and have encouraging safety and tolerability profiles. As such, we are focused on executing on our current liver programs and aggressively expanding our pipeline where we can. Last month, we announced top-line results for the Phase 2 SEQUOIA clinical study of fazirsiran for the treatment of liver disease associated with alpha-1 antitrypsin deficiency. The active treatment arm had results that were highly consistent with the ARO-AAT 2002 open label study, which we previously published in the New England Journal of Medicine. fazirsiran appears to be active against its target, with all treated patients achieving a high level of reduction of the mutant Z-AAT protein, which is known to be the root cause of AATD liver disease. This reduction over 12 months led to promising downstream changes in markers of liver disease, including reductions in inflammation, and 50% of patients experienced a regression in fibrosis. These encouraging results are exactly what we had hoped for. The only data point that was a bit difficult to interpret was in the placebo arm. There, three of eight patients with paired biopsies showed an improvement in fibrosis. We know that scoring fibrosis is a notoriously noisy measure. A way to smooth out such data is to ensure a large enough sample size. Unfortunately, with just eight patients, a single patient in either direction can lead to confusing percentages. We believe that is what happened here. Fortunately, we can look to previous studies for guidance on what fibrosis should look like in untreated patients. For instance, a previous natural history study that followed over 50 AATD patients showed about 15% had improvement in fibrosis. We believe that the 50% of patients who showed improvement in fibrosis on fazirsiran is a reliable measure because, A, the treatment groups had a larger sample size than placebo. B, the improvements in fibrosis was part of a larger data set that made sense together. Patients on fazirsiran had dramatic reductions in AAT monomer, globules, and they demonstrated decreased inflammation. The patients in the placebo arm showed none of these features. Takeda is now initiating a phase III study that will enroll up to 160 patients, which is designed to be sufficiently large to smooth that variability to approximately the levels expected on natural history. Arrowhead is eligible to receive a milestone payment from Takeda when the phase III study begins. During the previous quarter, two of our other partner programs generated milestone payments as they advanced into the next stage of development. Horizon Therapeutics enrolled the first subject in a phase I study of HZN-457, formerly called ARO-XDH, for the treatment of gout, earning Arrowhead a $15 million milestone payment. We earned a $25 million milestone payment from Amgen after the first subject was enrolled in Amgen's phase III trial, Olpasiran, for the treatment of cardiovascular disease. We believe in that program and in the potential of Olpasiran to help patients with the risk of cardiovascular disease associated with elevated levels of Lp(a). With the recent presentation and publication of positive phase II data, we determined that the timing was right to monetize our royalty stream associated with potential future Olpasiran sales. To that end, in exchange for rights to the Olpasiran royalties, Royalty Pharma paid us $250 million in cash upfront and up to $160 million in additional payments contingent on the achievement of certain clinical, regulatory, and sales milestones. In addition, we retained rights to $400 million in development, regulatory, and sales milestone payments potentially due from Amgen from the 2016 license agreement, including the $25 million milestone payment I just mentioned. During the quarter, promising new clinical data across three late-breaking presentations were presented at the American Heart Association meeting on three investigational candidates for cardiometabolic diseases, ARO-APOC3, ARO-ANG3, and Olpasiran. The totality of these data demonstrates the significant progress achieved in RNAi drug development, and they specifically suggest a potential future treatment paradigm where RNAi may be prominently leveraged in preventative cardiology. As I mentioned, a phase III study has already been initiated with Olpasiran. ARO-APOC3 is also being investigated in a phase III study against FCS, and we expect that 48-week study to be fully enrolled next quarter. We also expect end of phase II meetings this year to speak with regulators about phase III studies using ARO-APOC3 in SHTG patients as well as broad mixed dyslipidemia populations. My expectation is that we will launch those phase III studies at the end of the year. Similarly, I expect that we will move ARO-ANG3 into phase III studies in familial hypercholesterolemia this year. I also expect several data presentations from four phase II studies with these candidates throughout the year. Finally, we continue to make progress in our phase I/II study of ARO-C3, our candidate designed to treat several complement-mediated diseases. I expect to release initial data next quarter. Janssen has also made progress with their phase I study in JNJ-75220795, our partnered candidate against NASH, we expect a data disclosure that includes liver fat reduction this quarter. Turning to JNJ-3989, we have seen the media reports about Janssen deprioritizing HBV broadly, that is consistent with our understanding. We have not received a termination letter for our license agreement, it is our understanding that some legacy HBV studies are continuing, we do not know where JNJ-3989 will ultimately end up. We will assess our options and rights when Janssen decides the path forward for the program. With that overview, I'd now like to turn the call over to Dr. Javier San Martin. Javier. Thank you, Chris. Good afternoon, everyone. I want to describe the fazirsiran SEQUOIA data that we presented last month and then give an update on where we are with mid- and late-stage studies of our cardiometabolic candidates. Chris mentioned earlier the SEQUOIA data from the treatment arms were very encouraging and consistent with the prior data generated from the 2002 open label study. This is what we and our partner at Takeda wanted to see. Patients receiving 25, 100, or 200 milligrams of fazirsiran who have baseline fibrosis demonstrated a dose-dependent mean reduction in serum Z-AAT concentration at week 48 of 74%, 89%, and 94% respectively. All three doses led to a dramatic reduction in total liver Z-AAT with a median reduction of 94% at the post-baseline liver biopsy visit. PAS-D global burden, a histological measure of Z-AAT accumulation, had a mean reduction of 68%. Improvement in portal inflammation was observed in 42% of patients, while only 7% show worsening. 50% of patients achieved an improvement in fibrosis of at least one point by METAVIR stage. By week 48, patients receiving placebo who had baseline fibrosis saw no meaningful change from baseline in serum Z-AAT, had a 26% increase in liver Z-AAT, and had no meaningful change in PAS-D global burden. No placebo patient experienced an improvement in portal inflammation, while 44% experienced worsening. Three of the eight placebo patients experienced an improvement in fibrosis at the post-baseline liver biopsy visit. This finding highlights the known variability on histological fibrosis assessment. With a larger sample size, like in the planned phase III study, the rate of improvement in patients receiving placebo may more closely approximate results from natural history study of untreated patients with AATD. fazirsiran has been well-tolerated, with treatment-emergent adverse events reported today generally well-balanced between fazirsiran and placebo groups. There were no treatment-emergent adverse events leading to drug discontinuation, dose interruptions, or premature study withdrawals in any study group. Compared with placebo, no dose-dependent or clinically meaningful changes were observed in pulmonary function tests over one year with fazirsiran. These are all encouraging signs for the program and for patients. We know this is a progressive disease of the liver caused by one thing, the accumulation of a mutant Z-AAT protein, which cannot efficiently get out of the liver. The data suggests that fazirsiran can reduce the protein of new Z-AAT, and then the liver starts the process of breaking down and clearing the accumulated Z-AAT in the liver, reducing inflammation and ultimately regressing fibrosis. This is essentially the cascade of progressive liver disease in reverse. We believe that this reversal can only start with the removal of the insult to the liver, which is the accumulation of a mutant Z-AAT protein. This data represents a hope for physicians and their patients with this disease who have no approved treatment options. We also announced that Takeda is initiating a randomized double-blind placebo-controlled phase III study to evaluate the efficacy and safety of fazirsiran in patients with F2 to F4 fibrosis. Approximately 160 patients will be randomized 1-to-1 to receive fazirsiran or placebo. The primary endpoint of the study is a decrease from baseline of at least one stage of histological fibrosis METAVIR staging in the centrally liver biopsy done at week 106 in patients with METAVIR stages phase II, F2 or F3. I also wanted to give a brief update on where we are with our cardiometabolic candidates, ARO-APOC3 and ARO-ANG3. ARO-APOC3 is our investigational RNA therapeutic targeting apolipoprotein C-III or APOC3, being developed as a treatment for patients with mixed dyslipidemia, severe hypertriglyceridemia, and familial chylomicronemia syndrome. APOC3 is a key regulator of lipid and lipoprotein metabolism that inhibits lipoprotein lipase and mediates hepatic uptake of remnant particles in the LPL-independent pathway. In clinical studies, ARO-APOC3 improved multiple lipid parameters and may provide clinical benefit in a broad population with dyslipidemias. For ARO-APOC3, we have the following ongoing studies. The SHASTA-2 phase II study in patients with severe hypertriglyceridemia, the MUIR phase II study in patients with mixed dyslipidemia, and the PALISADE phase III study in patients with familial chylomicronemia syndrome. SHASTA-2 and MUIR are on schedule for data readouts later this year. These studies will inform the development path, regulatory interactions, and phase III study design. PALISADE continues to enroll patients efficiently, and we believe we will achieve full enrollment in the Q2 of 2023. It is a year-long study, so this will allow study completion in Q2 2024. ARO-ANG3 is our investigational RNAi therapeutic designed to silence the hepatic expression of angiopoietin-like protein 3 or ANGPTL3, being developed as a treatment for homozygous familial hypercholesterolemia or HoFH and heterozygous familial hypercholesterolemia or HeFH. ANGPTL3 is a key regulator of lipid and lipoprotein metabolism that inhibits lipoprotein lipase and endothelial lipase. ARO-ANG3 has a unique mechanism of action progress hypercholesterolemia, distinct from other LDL cholesterol-lowering therapies. For ARO-ANG3, we have the following ongoing studies. The ARCHES-2 phase II study in patients with mixed dyslipidemia and the GATEWAY phase II study in patients with homozygous familial hypercholesterolemia. All patients in the ARCHES-2 have completed treatment, and we should have data processed and analyzed in the middle of the year. GATEWAY is fully enrolled, and we should have initial data around the middle of this year as well. We intend to interact with regulator about our plans for phase III studies this year. I will now turn the call over to Dr. James Hamilton. James. Thank you, Javier. We announced last week the initiation of a phase I/II study of ARO-MMP7. I wanna talk about that first. ARO-MMP7 is designed to reduce expression of matrix metalloproteinase 7, or MMP7, as a potential treatment for idiopathic pulmonary fibrosis, or IPF. MMP7 is thought to play multiple roles in IPF pathogenesis, including promoting inflammation and aberrant epithelial repair and fibrosis. Significant unmet medical need exists for patients with IPF who experience progressive decline of lung function despite current therapies. AROMMP7-1001 is a phase I/IIa, single ascending dose and multiple ascending dose study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ARO-MMP7 in up to 56 healthy volunteers and in up to 21 patients with IPF. Moving on to our two other pulmonary programs, ARO-MUC5AC and ARO-RAGE, our investigational RNAi therapeutics designed to reduce production of mucin 5 AC, or MUC5AC, and the receptor for advanced glycation end products, or RAGE, respectively, as potential treatments for various muco-obstructive and inflammatory pulmonary diseases. As Chris mentioned, we are on schedule to have initial data from the healthy volunteer portion of the phase I/II studies in the H1 of this year. The healthy volunteer portion of these studies has two parts, a single ascending dose part and a multiple ascending dose component. The studies are designed to assess safety and tolerability, pharmacokinetics and pharmacodynamics. We will be assessing pharmacodynamics by measuring available biomarkers in bronchoalveolar lavage fluid, induced sputum, and for RAGE, we are also measuring serum sRAGE protein. The second portion of the studies is in patients with moderate to severe asthma. We recently initiated enrollment in asthma patient cohorts in both the ARO-MUC5AC and ARO-RAGE studies. Initial data should be available around the end of the year. Moving on to ARO-C3, which is our investigational hepatocyte-targeted RNAi therapeutic targeting hepatic C3 expression as a potential treatment for complement-mediated hematologic and renal diseases. We remain on track to report data from part one of the study in healthy volunteers in the H1 of this year. Based on an analysis of data from the healthy volunteer single and multiple escalation dose cohorts, we anticipate selecting doses for the part two open label patient cohorts this month, and we are on track to open patient cohort enrollment in the H1 of this year. I will now turn the call over to Ken Myszkowski. Ken? Thank you, James. Good afternoon, everyone. As we reported today, our net loss for the quarter ended December 31st, 2022 was $41.3 million, or $0.39 per share based on 106 million fully diluted weighted average shares outstanding. This compares with the net loss of $62.9 million or $0.60 per share based on 104.5 million fully diluted weighted average shares outstanding for the quarter ended December 31st, 2021. Revenue for the quarter ended December 31st, 2022 was $62.5 million, compared to $27.4 million for the quarter ended December 31st, 2021. Revenue in the current period primarily relates to our collaboration agreements with Amgen, Horizon, and Takeda. Revenue is recognized as we complete our performance obligations, which include managing the ongoing AAT phase II clinical trials for Takeda and delivering a phase I-ready candidate to Horizon. There remains $107 million of revenue to be recognized associated with the Takeda collaboration, which we anticipate will be recognized over the next one to two years. Horizon enrolled the first subject in a phase I trial of HZN-457, formerly known as ARO-XDH, which triggered a $15 million milestone payment to us. Amgen enrolled the first subject in its phase III registrational trial of Olpasiran, which triggered a $25 million milestone payment to us. Both milestone payments were received in the Q2 of fiscal 2023. Revenue in the prior period primarily related to the recognition of a portion of the payments received for our license and collaboration agreements with Takeda and Horizon. Total operating expenses for the quarter ended December 31st, 2022 were $104.7 million, compared to $90.8 million for the quarter ended December 31st, 2021. The key driver in this change was increased candidate costs and salaries as the company's pipeline of clinical candidates has both increased and advanced into later stages of development. Net cash used by operating activities during the quarter ended December 31st, 2022 was $75.5 million compared to $61.3 million for the quarter ended December 31st, 2021. The increase in cash used by operating activities is driven primarily by higher research and development expenses. We expect our operating cash burn to be $70 million-$90 million per quarter in fiscal 2023 and capital expenditures up to $200 million as we approach completion on our footprint and expansion projects, including GMP manufacturing. Turning to our balance sheet, our cash and investments totaled $617.6 million at December 31st, 2022, compared to $482.3 million at September 30th, 2022. The increase in our cash and investments was primarily related to the $250 million payment from Royalty Pharma, offset by our operating cash burn along with continuing capital projects. Our common shares outstanding at December 31st, 2022, were 106.1 million. With that brief overview, I will now turn the call back to Chris. Thanks, Ken. We're making good progress on our 20 in '25 initiative, where we expect to have 20 individual drug candidates in clinical trials or at market in the year 2025. We currently have 12 drug candidates in clinical studies, six of which are wholly owned and six are partnered. I expect that 12 to become 15 or 16 by the end of this year. I mentioned ARO-DUX4 moving into the clinic next quarter. I expect two or three additional new drug candidates this year. We have never talked about them publicly. Having such a large clinical pipeline provides us with a broad base from which to build value and spread risk. It also gives us consistent opportunities to share data and progress. In the near term, we think these opportunities will include the following: phase I NASH data from J&J-0795 this quarter. fazirsiran SEQUOIA full 12-month biopsy data in the Q2. Initiation of ARO-HSD phase IIb in Q1 or Q2. Early ARO-RAGE phase I/II data in the Q2. Early ARO-MUC5AC phase I/II data in the Q2. Early ARO-C3 phase I/II data in the Q2. Initiation of the ARO-DUX4 phase I/II study in the Q2. Disclosure of our next cell type and supporting data in the Q2. ARO-APOC3 data throughout the year. ARO-ANG3 data throughout the year. Initiation of two to three new phase I studies toward the end of the year. Initiation of JNJ-75220795 phase II in Q3 or Q4. Early ARO-MMP7 data in Q4. Initiation of ARO-ANG3 phase III studies in Q4. Initiation of additional ARO-APOC3 phase III studies in Q4. As you can see, we expect a busy 2023. Thank you for joining us today, and I would now like to open the call to questions. Operator? Operator? Our first question comes from the line of Eliana Merle of UBS. Your line is open, Ellie. Hi. Thanks so much for taking the question. Just in terms of the data in the Q2 from the pulmonary franchise, I guess, what exactly are we getting in terms of the number of patients and dose levels? And what are you looking to see? I guess, what degree of lowering at, say, these dose levels, is sort of the target levels that you're looking for and will confirm, I guess, kind of this target engagement that we're hoping to see? Thanks. Look, I don't know that we have a target knockdown, threshold that we're looking for. You know, this is our first, these will be our first, data in human subjects, we're looking to see what sort of knockdown we get. Again, I don't know that we have a bogey. James, do you wanna talk about some of the cohorts that we may be seeing? Sure. Right. We'll have data in the SAD cohorts for the first four dose levels and then likely as well the MAD cohorts through at least the first three cohorts, the two-dose cohorts. That's all in the healthy volunteers. We won't have any patient data at that point. Great. Thanks. Sure. Thank you. Again, to ask a question, please press star one one on your telephone. Again, that's star one one on your telephone to ask a question. Our next question comes from the line of Maury Raycroft of Jefferies. Your line is open, Maury. Thanks for taking my question. I had a question about the pulmonary data as well. Wondering if you expect the bronchial lavage data to correspond with the RAGE serum PD biomarker data. I guess maybe talk a little bit more on just what kind of proof of concept we should be looking for in this update. James? Yeah. I think directionally, I would expect based on what we've seen in animals, in monkeys specifically, that the sRAGE lavage data should. Directionally behave the same as the serum data. My take on that is that, you know, we'll see what the data look like, but my sense is that the lavage data may give us more accurate knockdown because it's local, of course. The challenge with the systemic is that there may be extra pulmonary sources of RAGE, and so that may muddy the data a bit. That will give us a better idea of duration because, you know, we're not bronching these individuals more than once. Got it. Okay. That's helpful. Also just with the J&J media reports, I'm wondering if you've had any discussions with J&J regarding JNJ-3989 ongoing studies and have a sense of when they could make a decision on the program. What are some options you're considering if J&J terminates the license agreement? This is all new for us, I don't have too much to comment on this at this point. Again, we understand that they are deprioritizing HBV broadly. You know, this doesn't have only to do with our candidate, as I understand it. They do not have... Again, my understanding and Patrick O'Brien can correct me if I'm wrong here. My understanding is that they don't have the right to sublicense this, but they could assign it. We'll see what they decide to do there. If they do decide to assign it requires our approval, otherwise it will come back to us. We don't know what their, what their goals are here, and we'll just have to wait to see. Look, you know, we, we believe in that program. I think that drug clearly does what it's designed to do. You know, we're seeing substantial reduction in viral antigens. I think that's important. That is maybe the critical component to getting to a functional cure. It's not the only component, but I think it's the, it's the critical one. They were interrogating a number of different strategies to, you know, to see what they can combine with that to get to functional cures. We look forward to seeing more of those data because, you know, we are only so close to it at this point, of course. Got it. Okay. Makes sense. I'll hop back in with you. Thanks for taking my questions. Yeah, thank you. Thank you. Our next question comes from the line of Mayank Mamtani of B. Riley. Your line is open, Mayank. Hi. Thanks for taking our questions. Looks like a busier 2023 for you than last year. Maybe just following up on the pulmonary programs. On the safety and tolerability data that we'll have for RAGE and MUC5A, could you talk about sort of the implications of that broadly for your delivery system? Just maybe remind us if the nebulizer system is the same across the different programs. A second part question on the MMP7, what is the frequency of administration you're looking to target there? As you know, in IPF, now there's a lot of progress in the pipeline with some antibody approaches also coming in. Sure. Yes. I think, you know, the safety data that we will have for RAGE and MUC5AC, I think, while it will be candidate specific and target specific, I think will be applicable to the broader platform, and, you know, will help to support the pulmonary delivery platform generally. In terms of the nebulizer question, It's the same nebulizer system that we're using across the three, different programs. It's different than what we used with ARO-ENaC, so this is a more efficient nebulizer, versus what we used with ENaC. There was a third question there, I think. MMP7 dose interval. The initial dosing interval for MMP7 is every two weeks in the MAD cohorts. In the SAD, of course, we just do single doses, we're investigating day one, 15 and 29 in MMP7. It's similar to what we're doing in the MAD cohorts for MUC5AC. That may not be the dosing regimen going forward. That's sort of a more intensive regimen, consistent with what we used in the animals to generate maximal knockdown. We'll have to see what the duration of knockdown is after both a single dose and after the multi-dose administration. Got it. Then just a quick follow-up on JNJ-75220795. Could you just remind us what the target there is and sort of the progress, how far along that program is? I know it's a J&J partner program. Then just broadly on the partnership with J&J, is it sort of program by program, I'm assuming, and whatever happens with JNJ-3989 has no implications on how things may progress with JNJ-75220795? Yeah, those are different divisions within Janssen. The target is PNPLA3, maybe the most genetically validated target for NASH. They are in a phase I study that includes a SAD as well as a MAD portion. It is my expectation that we can start to report at least certainly some SAD data this quarter. Okay. Thanks for taking our question and look forward to the update. You're welcome. Thank you. Our next question comes from the line of Joel Beatty of Baird. Your line is open, Joel. Again, Joel Beatty of Baird, your line is open. Hi there. Can you hear me? Yes. Great. For the lung programs, and the data coming in Q2, could you elaborate on, you know, how meaningful the data is for other programs? In prepared remarks, you talked about eight or nine programs that could come for lung. How de-risking is this data that we get in Q2? I think it's substantially de-risking. You know, this is, this will be the first, you know, clinical data from our lung franchise. The structure of these candidates is really quite similar between MMP7, MUC5AC, RAGE, and future ones. They are simple, conjugates, as you know. It's simple RNAi trigger that is chemically modified, linked to a targeting moiety. To the extent that it is well-tolerated and can get into these pulmonary epithelial cells, I think it is telling as it relates to future candidates. You know, these cells don't care what the sequence of the RNAi trigger is. Once you get into this cell, and get loaded into the RISC complex, it can, you know, it can be any sequence. I think that it is a substantial de-risking event, again, to the extent that we do show clinically relevant, knockdown, in a well-tolerated fashion. Great. That's helpful. For AAT, are you able to discuss the powering assumptions or otherwise just kind of speak at a high level as to what gives you confidence in the powering for the 160 patient registrational phase III that's planned? Yeah. I can give you a high level concept, but this is, you know, Takeda's protocol design, and it is already in the public domain in ClinicalTrials.gov. Essentially, if you look at what Takeda has been thinking is taking a conservative approach for the active treatment group, and then not as conservative for the placebo group, but with that, make the assumptions and the typical standard deviations that are expected, and with that in mind, the power calculation. They took, we think, a prudent conservative approach with regard to the duration, which is 106 weeks, so two years essentially, and the sample size and the patient population they selected. It's not just the assumption, but it's the assumption in the context of the sample size of 160 patients, a two-year observation, and all patients will have at least an F2 fibrosis stage based on the metabolic. When you look at the totality of the study design, we believe the study is well set to show the benefit in fibrosis reversal. The details for Takeda eventually will come out with more details. Great. Thank you. Thank you. Our next question comes from the line of Madhu Kumar of Goldman Sachs. Your line is open, Madhu. Well, hey, great. Thanks for taking our question. I guess our first one relates to the idea in the lung of which cell type matters, and how do you think about in various pulmonary indications targeting the lung epithelium or specific cells in the lung epithelium versus, say, other cell types that are just present in the lung, particularly immune cells in the lung? How do you kind of thread that needle? Secondly, along the questions of threading the needle, how do you think about the kind of Goldilocks phenomenon of knockdown? These pretty powerful inflammatory modulators, where you wanna suppress them enough so that you reduce the kind of autoimmune functions, but you don't suppress them so much that you reduce the viral protective functions. How do you think about kind of that balance there? Sure. Well, first of all, regarding the epithelial cells that are the cells that we're trying to target, you know, those are generally the cell types where we're looking for targets. We're looking for targets that are expressed by lung epithelial cells. If there's a target that is, you know, related to a disease that we could knock down, that's the ideal situation. I think that's where our system performs best, is in getting into those cell types and knocking down targets expressed in pulmonary epithelial cells or some of the derivatives, something like the basaloid cells in that are more specific to an IPF patient population. Right now, we are not targeting any gene targets in, you know, macrophages or other immune cells in the lung. We're pretty focused on the epithelial or epithelial cell-derived types of cells. The other question was about modulating inflammation. For something like RAGE, that, you know, knocking down RAGE, like you said, could be fairly powerful as an anti-inflammatory. There are other, there's redundancies built into the system. I think some of the innate immune functions that would be inhibited by silencing RAGE can also be activated through a TLR4 pathway. You're not completely wiping out the innate immune system altogether. There is some redundancy there. Okay. Thanks so much for taking our questions. Sure. Thank you. Our next question comes from the line of Mani Foroohar of SVB. Your line is open, Mani. Hi, assuming this is referring to Mani Foroohar, this is Vivian Tsang. First question, we had a question regarding the pulmonary program. What would be the level of knockdown that will be expected in order to reach p-functional benefit as in a clinical setting? We don't know the answer to that. Look, there are advantages and disadvantages to being pioneers here. The advantages are that we're the first ones. The disadvantages are that, you know, no one's done this before, and so, you know, we'll be learning the field as we go. I don't have a good answer for you on that one, unfortunately. All right. I guess we'll have to ask again maybe a little later. Thanks. I guess maybe just a different question in terms of the HBV program. Should the asset be returned by J&J, what would be your development plan? Would you consider, you know, given that most assets in this particular sector are partnered, especially for the combination program, would you consider developing it internally or seeking out a new partner? Yeah, it's a good question. Look, again, as I mentioned, that drug is doing what it's designed to do, and that's exciting. Janssen has done a phenomenal job with a number of very large studies. They're sitting on a ton of data. We are familiar with some of those data, but not all of them. It's hard for us to make. It's impossible for us to make a decision about how we might develop that drug until we get into those data. We are certainly interested, again, because the drug is it appears to be doing what we intended it to do. We just have to take a look at all the data to see what the path forward, will be. I do firmly believe that there is a path forward. I just don't know what it is until we see the data. Thank you. I guess lastly, would there be any sense of timing in terms of maybe when you'd be able to either get maybe more clarity from J&J or access to the data so you could make an informed decision? I don't have an answer for that, unfortunately. I don't know what their timeline is. As I mentioned in prepared remarks, my understanding is that there are some ongoing studies. I assume that those are still ongoing, but I don't know, to be honest. I think this is all happening in real time and my expectation is that we'll have better clarity from Janssen over the next, you know, coming weeks. All right. Thank you. You're welcome. Thank you. Our next question comes from the line of Luca Issi of RBC Capital Markets. Your line is open, Luca. Great. Thanks so much for taking my question. I have two. Circling on AAT, circling back on a prior question, Javier. Can you just talk a little bit more about the powering assumption here in the phase III? You know, at 160 patients in the primary endpoint at two years, what is the minimum delta in fibrosis between the active arm and placebo that is actually sufficient to hit the stat? Any color there will be great. On DUX4, can you just talk a little bit more about that program? I think in the past you have mentioned that expression can be quite variable there. Wondering how you're planning to mitigate the risk, and more broadly, how confident are you in that program? Sure. Yeah. Hi, Luca. I don't know how much detail I can provide on the specifics that the Takeda team and the statistician, the work they did to power the study or to size the study with 160 patients. Like I said, the primary endpoint or the primary analysis is at two years, 106, when all patients with F2 and F3, that would be about 110 or so, complete the two-year study. That gives you really, for what we learned so far and, you know, we can take this, 50% reduction in fibrosis that we observed twice in two different studies with the same aim and similar patient population as a good point of reference, I would say. You know, you need to look at the natural history data versus the SEQUOIA data and go somewhere in between. If you do that exercise, you will come out with the same number, more likely. That's how I will address this comment. Yeah. Importantly, as Javier mentioned, that two year time point is at around 110 patients, not the full 160. Importantly, it was powered based on that. Given their assumptions, they determined that 110 should be sufficient. James, Sure, yeah. I can take the DUX question. It's correct that the expression of DUX4 is stochastic, and so the measurement of the protein in the muscle and the downstream DUX4-affected genes can be challenging, as at least one other company has demonstrated. That was one of the reasons, if you recall, that we wanted to be sure that we had the tox coverage to cover a longer phase II study. If we weren't able to see any knockdown in gene expression, that we could do a longer study and see some proof of concept efficacy with imaging, specifically MRI or with functional endpoints, things like reachable workspace. That we now have that tox coverage at least from the chronic monkey study, and I think the chronic rat readout should be available shortly. We have the ability to design a study that not only could potentially give us biomarker readouts if we're able to measure DUX4 and downstream gene expression, but also a study that would have an MRI and functional endpoints built into it as well. Got it. Thanks so much. Thank you. Our next question. Sorry. Our next question comes from the line. One moment. Our next question comes from the line of Prakhar Agrawal of Cantor. Your line is open, Prakhar. Hi, this is Prakhar from Cantor Fitzgerald. Thanks for taking my questions. First on RO80, how long do you think will it take to enroll the phase III trial, the clinical trial entry for, it suggests primary completion date of March 27th. That would imply roughly two years for enrollment. Is that the right proxy to think about the timing of this readout, or would the timelines be expedited? I had a quick follow-up. Yeah, you know, I think it's inappropriate for us to opine on that, since Takeda will be running that. I think probably best to ask them what their expectations are. Okay. Second on our APOC3. Any comments of how you're thinking about the trial size and duration for the for the CV outcomes trial? What do you think you need to show on the CV outcomes for that asset to have a broad uptake in the NASH population? Thank you. Yeah, we're at the very beginning of that process, but as you know, it's not a simple process. We will work with a group of experts who are at the beginning of establishing a governance on how to design and execute that study. As we said during this call, we are wrapping up the phase II study within the next quarter or two quarters. That will be the way that we will define the study design. We're planning to have interaction with the FDA to talk about that this year. The expectation is that we will start this study in 2023. It's the beginning of a process, a lot of work that need to be done. Some important decisions that will be related to the specific of the study design, how long it will last. It's likely to be on a, of course, an event-driven trial, as most of these studies, are. A lot to come, a lot to talk about within the next few quarters. Yeah. There are at least a couple things that are gating for us to figure out what, you know, what those CBOTS might look like. One thing is, look, we still haven't read out the entire phase II studies yet. We have interim analysis that looks quite positive and we're excited about, but we need to finish those studies and see what those look like. That's the first. Second is that we haven't had discussions with the FDA about their expectations. We have to have those. I think once we get through those two, those two issues, we can have a better idea about what these things might look like. Understood. Thank you for taking the questions. Yep. Thank you. At this time, I'd like to turn the call back over to Dr. Chris Anzalone, President and CEO, for closing remarks. Sir. Thanks everyone for joining us today, and have a nice evening. This concludes today's conference call. Thank you for participating. You may now disconnect.