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 Finance and Investor Relations for Arrowhead. Please go ahead, Vince.

Thank you Tania. And good afternoon, everyone. Thank you for joining us today to discuss Arrowhead's results for its fiscal 2022 second quarter ended March 31, 2022. With us today from management are 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 -- will provide an update on our mid-and later stage clinical pipeline. Dr. James Hamilton, our Senior Vice President of Discovery and Translational Medicine will provide an update on our earlier stage program and Ken Myszkowski, our Chief Financial Officer, will give a review of the financials. We will the call up to your questions. 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. 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. I want to start by saying thank you to all those who joined yesterday in Verona, Wisconsin for the ground-breaking ceremony at the site of our new manufacturing and lab facilities including Mayor Diaz, Secretary Hughes and Governor Evers. Many people from BioForward, studies the cities of Madison and Verona and the state of Wisconsin have been very supportive of Arrowhead over the years. We appreciate their partnership as we grow our business and capabilities to support the potential future commercial opportunities for our investigational RNAi based medicines. To that end, we announced yesterday that we announced yesterday that we received awards of up to $18.5 million in incentives to invest in the local region and create new jobs. These incentives help to defray some of the build out costs for our Verona facility but importantly, to demonstrate the commitment of the region to expand the number of highly skilled jobs and attract talent. We have been very impressed with the quality of the workforce and intend to be a long time contributor to the growing biotech ecosystem in Wisconsin. So what does this new manufacturing facility and associated office and lab facility do for Arrowhead? First, it increases our control over manufacturing at all scales, which should decrease costs and increase our speed and flexibility. Second, it enables us to better control IP as we develop new methods of manufacturing aimed at decreasing costs, and increasing purity and scale. Third, it makes us a better and more complete partner to those companies bringing the drugs we create to patients and fourth, it provides additional specialized lab space to enable continued growth and innovation as we bring RNAi to new cell types and address new diseases. This is…

Thank you, Chris and good afternoon, everyone. I will provide updates on enrollment for the VISTA set of studies for ARO-ANG3 and the summit study for APOC3 and get some forward guidance on anticipated timelines. I will start with the VISTA studies of ARO-ANG3, our investigational medicine designed to reduce production of angiopoietin like protein three as a potential treatment for patients with dyslipidemia. There are currently two active studies ARCHES-2 in patients with mixed dyslipidemia and GATEWAY impatient with HoFH. ARCHES-2 is a double-blind placebo controlled Phase 2b study. ARCHES-2 is a full enrolled with 204 patients with triglycerides between 150 and 500 milligrams per deciliter and non-HDL cholesterol greater than 100 milligrams per deciliter or LDL cholesterol regular 70 milligrams per deciliter. The in-randomized in a 3:1 ratio to receive a subcutaneous injection of ARO-ANG3 or placebo on Day 1 and week-12 with those levels ARO-ANG3 350 milligrams, 100 milligrams and 200 milligrams are being evaluated against placebo. The duration of the study is approximately 42 weeks from screening to the week 36 end of study examination. After completing the week 36 -- participant will be eligible to continue in an open label extension period. We anticipate that ARCHES-2 will be completed around the end of 2022 and top line data will be available to share in the first half of 2023. The next ARCHES studies GATEWAY, an open label Phase 2 clinical study to evaluate the efficacy and safety of investigational ARO-ANG3 in upto 16 such as with HoFH. To those level of ARO-ANG3 200 and 300 milligrams will be evaluated in such as with documented HoHF based on genotype or clinical criteria, and with fasting LDL cholesterol greater than 100 milligrams per deciliter and fasting triglycerides, less than 300 milligrams per deciliter. ARCHES will receive a…

Thank you, Javier. I want to give updates on a few of our early stage clinical programs and preclinical programs. Let's start with ARO-C3 our investigational RNAi therapeutic designed to reduce production of complement component 3 or C-3, as a potential therapy for various complement mediated diseases. During the quarter, we dosed the first subjects in a clinical study. This is a Phase 1/2 placebo controlled dose escalating study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of ARO-C3 in upto 24 adult healthy volunteers and up to 24 patients with paroxysmal nocturnal hemoglobinuria, or PNH and up to 14 adult patients with complement mediated renal disease. In part one healthy volunteer will receive a single subcutaneous injection of ARO-C3 or placebo. In part two, eligible subjects with PNH or complement mediated renal disease will be enrolled to receive open label ARO-C3. We have completed dosing in three of four planned cohorts in part one, and expect to dose escalate to the final planned cohort. We intend to initiate part two in patients when we have selected a dose from part one and the next quarter or so. Moving on to our first plan, skeletal muscle targeted candidate ARO-DUX4 our investigational candidate designed to target the gene that encodes human double homeobox 4 protein or DUX4 as a potential treatment for patients with facioscapulohumeral muscular dystrophy, or FSHD. FSHD patients have no real therapeutic options so we are moving as quickly as possible to begin clinical studies. However, it has been challenging for the field to identify a reliable biomarker of DUX4 expression, or of disease activity in patients with FSHD. Thus, it is likely that Phase 1 results may not be informative with regards to pharmacodynamic biomarkers, and may only inform on initial safety. Longer Phase 2 studies may…

Thank you, James and good afternoon everyone. As we reported today, our net income for the three months ended March 31, 2022 was $44.4 million or $0.41 per share based on $107.9 million fully diluted weighted average shares outstanding. This compares with a net loss of $26.8 million or $0.26 per share, based on $103.9 million fully diluted weighted average shares outstanding for the three months ended March 31, 2021. Revenue for the quarter ended March 31, 2022 was $151.8 million compared to $32.8 million for the quarter ended March 31, 2021. Revenue in the current period primarily relates to the recognition of $120 million upfront payment received under our collaboration agreement with GSK, and recognition of a portion of the upfront payments received from our license and collaboration agreements with Takeda and Horizon. The upfront payment for GSK was recognized as revenue entirely in this quarter as our performance obligations are substantially complete. Revenue for our collaboration agreements with Takeda and Horizon will be recognized as we complete our performance obligations, which include managing the on-going AAT Phase 2 clinical trials for Takeda and delivering a Phase 1 ready candidate to Horizon. There remains $167.6 million of revenue to be recognized associated with the Takeda collaboration, which we anticipate to be recognized over approximately two to three years. And there remains $20 million of revenue to be recognized for Horizon, which we anticipate will be recognized by the end of calendar 2022. Revenue in the prior period, primarily related to a recognition of a portion of the milestones received from our licensing collaboration agreements, with Janssen and Takeda. Total operating expenses for the quarter ended March 31, 2022 were $110.3 million, compared to $61 million for the quarter ended March 31, 2021. This increases primarily due to increased clinical…

Thanks Ken. And thanks to all of you for joining us today. The markets go through cycles of intense pressure as they are today, investors seek value. Each investor needs to define for themselves what value means. But I see value in a biotech company through several questions. Does a company have multiple potential drugs? Are those potential drugs built on a platform with known safety and activity parameters? Are those drugs addressing real unmet medical needs in a unique way? Does the company have sufficient capital and access to capital? Does the company have a track record of execution? Does the company have the ability and commitment to continued pipeline growth? And is the company focused on long term growth and getting drugs to patients? These may seem simple and straightforward, but precious few companies our size can answer all of these questions in the affirmative. I believe that we do. And by focusing on core principles such as these, Arrowhead is well positioned to do right by the patients we serve and create substantial value for our shareholders. I believe we have a pipeline that is substantially larger than any company our size and larger than most companies several times our size. Everything we do is built on RNAi and the TRiM platform, both of which are increasingly validated clinically. Whether addressing chronic HBV, where it is thought that someone in the world dies every 30 seconds from complications of infection, or cardiovascular disease, we are addressing clear unmet medical needs. And we believe we are the first to use RNAi against every target we are going after. We have a strong balance sheet and importantly, access to on-going capital as our current partnerships mature and trigger milestone payments. We have demonstrated our consistent ability to move rapidly to the clinic and into later stage trials. Our pipeline continues to grow with three new candidates entering clinical studies over the past six months alone, and we expect more through the end of the year. While the current market dynamics are uncomfortable, we are laser focused on getting our current and future drug candidates to the patients who need them, and trust that this commitment will create substantial value for our shareholders. Thank you for joining us today, and I would now like to open the call to your questions. Operator?

Our first question comes from Maury Raycroft of Jeffries. Your line is open.

Hi, thanks for taking my questions. I was going to ask a question on A, do you talk more about the expectations for the upcoming regulatory interaction in the spring added the Phase 2, 12-months biopsy readout and how you're planning on updating investors after the meeting has completed?

Javier, you want to address them.

Sure. As you know why, why can we Takeda and Takeda is leading the international with the FDA from now on. So they will lead the next meeting, which is the end of Phase 2 meeting that will happen within the next few months. And that meeting, as you know, the key discussion points will be the design of the Phase 3 study that includes endpoint sample size, those. So that's the start with regard to regulatory, we expect to have a decision and an agreement at one point in the second half of this year. This study 2001, which was the dose range study for the dose ranging component is completed and it would be part of the package. As Chris said, this study will be completed in terms of biopsy by July of this year. So we have everything we need to have this meeting with the FDA. Takeda is doing a fairly good job and we're collaborating very closely. So I think we will we'll have more about this in the next call for sure.

And oftentimes to be clear, as Javier said, the dose finding portion of that study has read out and given those data Takeda has initiated interactions with the FDA. So that's already begun. They will we expect them to have a formal meeting in the next coming months. And so we'll see where, where it helps, we'll see how that Phase 3 is designed. The whole we look forward to seeing the biopsy data sometime this fall, from the SEQUOIA study that as you know, is blinded so we haven't seen anything there. And that's just that's, that's a bit of a wildcard; we look forward to seeing what those look like. And I think we have to focus on or Takeda has to focus on designing the space three right now. And then once we see those data from the square box biopsy, we'll see if that if that affects their actions going forward with the FDA.

Got it. That's helpful. And will this, will the upcoming and the Phase 2 meeting will that determine what the endpoint is? And when you get the biopsy data will be could the endpoint change or I guess how should we think about that?

Yes, exactly that inter Phase 2 meeting will, the goal is to have an agreement on this specific Phase 3 study design, which will include primary endpoint, the duration, the goals, and the sample size. So all the details about the Phase 3 study, and also the inter Phase 2 will include CMC conversations. So everything needs to be in place to set the registration, Phase 3 study right after that meeting.

Got it. Okay. And maybe just a quick question on DUX4 just wanted to clarify if you're seeing any signals in healthy volunteers prior to starting part two, or are you just being conservative waiting for the chronic tox data?

So if you're asking about DUX4 that study has not yet started in the clinic. Yes. So that's still preclinical. We have not enrolled any healthy volunteers, yet it just given in the, in the prepared remarks in James's prepared remarks, as he, as he described, we learned from prior clinical studies that that it's difficult to measure DUX4. And so given that it made sense to us to maybe go a bit slower on the front end, so we can go faster on the on the later stages. And so we're waiting to see what those chronic talks data might look like before we before we design the study and initiate the study.

Got it. Okay, that makes sense. Okay. Thanks for taking my questions.

Welcome.

Our next question comes from Luca Issi of RBC Capital. Your line is open.

Well, great. Thanks so much for your question. Maybe circle back on Maury’s question earlier maybe ask a little bit more directly. Is there a scenario where you can file early for A-180 in the second half of the year, should the biopsy data check the box given and how you have breakthrough therapy designation? Again, any call there was great. And then maybe on hepatitis B, I think we've seen J&J obviously discontinuing their collaboration with Bavarian Nordic. So wondering if that's just one off or maybe it reflects like lower interest, interest in the space for them more broadly. Also, any color there will be great. Thanks so much.

Sure. So when we take HBV first. We don't see any evidence that that the J&J is losing interest in HBV. To the contrary, they are working as fast as ever, and they're expanding these studies, it almost seems like every day into different patient populations and sites. And so we see, we see a strong interest in HBV. I don't know what the, what led them to terminate those other partnerships. But ours is going strong, and we still feel confident about our drug, and we feel competent about them as a partner in their commitment to the disease. So, we're still going to blaze in there. With respect to AAT, it's hard, I don't really want to speculate on what we could do with, with those biopsy data, just because there's too many unknowns. Right now, we indicate it together have to focus on negotiating with the FDA on finding common ground with the FDA on what a Phase 3 study will look like. How large study it is, what the endpoints are, how long a study it is, in the like, we think we'll get there because the FDA has been quite collaborative so far. And as you point out, we do have breakthrough therapy designation, so we can have these discussions. So we're confident that we will, that we will work at Takeda, we'll design a enrollable good study that will fit that will that will be beneficial to the ultimate drug, I think. Now, having said that, you look, we look forward to seeing what this biopsy data look like. And once all that is unblinded, we indicate it together; we'll take a look at it. And it's certainly conceivable that you should those should those data be extraordinarily compelling that it could lead to, to discussions with the FDA, under our under our designation with them. So it's too early to, to predict what those could mean. But we're certainly interested in looking at where and we are excited to see what those data are. And we're excited to continue the conversations with the FDA.

Super helpful. And then maybe if I may on capital expenditure. I think in the past, you've got an $80 million to $90 million for fiscal 2022. However, it sounds like you're lowering that guidance. So wondering if you can give us a little bit more kind of quantitative color and that, that'd be great. Thanks so much.

Yes, we are lowering our guidance on capital expenditures this year. As I had mentioned in our in our remarks, the two major projects had just recently started. So we might expect our CapEx to be something like 25% to 50% of what we originally estimated. And as I said those projects will move quickly at the end of this year we'll increase our capital expenditures in fiscal 2023.

Super helpful. Thanks so much guys.

You're welcome.

Thank you. Our next question comes from Madhu Kumar of Goldman Sachs. Your line is open.

Hi, this is Mario on for Madhu. We have a handful of questions. So first, can you remind us that useful from the AAT program in 2022? More specifically, can we expect top line data at a medical meeting and disclosure of regulatory interactions?

Javier, are you interested?

So we will present the data in 2002 to the end of June in the meeting in London, so that will be the I think at this point, the only presentation, we may disclose when we complete the 2001 analysis the second half of this year. And with regard to the regulatory deduction, we say within the next few months, we have Inter phase meeting and the expectation is to start the Phase 3 this year. So that's…

Right. Yes. So I don't think we're we don't expect you to, to provide a blow by blow up. But once we have alignment with the FDA on what that basically looks like, we'll be happy to, of course, disclose that.

And I wanted to also say that we're working on the manuscript in 2002. So we're in the final preparations here to submit that manuscript. So hopefully there will be published this year.

Allright, thank you. And then just maybe jumping the gun for the pulmonary R&D Day in a few weeks but what is the clinical proof-of-concept look like to you for the lead loan programs?

James, do want to address that?

Yes, sure. I think we will be talking a lot more about that as the R&D day, end of the month. But in terms of what we're really looking for, in both of these programs, and Phase 1 is proof-of-target engagement, that we can knock down the targets, and that we have a good dose response there. So I think that's the most important thing we expect to get out of Phase 1.

And we have circulating biomarkers there. So it'll be much more straightforward to look at that with RAGE and MUC5AC was looking at.

And like I said, two more questions and how should we think about the upcoming Olpasiran ? And then how far do you plan to take ARO-ANG3 and ARO-APOC3 and cardiovascular disease? Is there any plan to perform…?

Yes, so I'll take that one first. Look, we, it is our plan right now to take ARO-ANG3 and ARO-APOC3 through to registration. We think those are potentially very important drugs. And we think that they that they will provide, important new tools to cardiologist lipid clinics. And I've said this in the past and it sounds I don't want to overstate it, but it really feels like those. Those are important drugs. And so we are fully committed to those. And I think we're going to commercialize those. The first question was with respect to Olpasiran. I don't know what else I can tell you this. We haven't seen any data. So there's nothing like I can accidentally tell you. We're waiting to see what those data look like, just like the rest of us. It's like the rest of you. The Phase 1 data were compelling. That's a that looks like it's a very potent drug candidate. I think the genetic validation with respect to that target is clear. That drug or that drug candidate appears to be doing what we want it to do. It appears to be well tolerated. And so we're excited to see those data and we and to be honest, we fully expect for Amgen to push that into a pivotal study quite quickly.

All right, thanks for taking the questions.

And our next question comes from Ellie Merle of UBS. Your line is open.

Hey guys, thanks for taking the question. Just a follow up on the RAGE and MUC5AC programs. I guess if you're starting to dose patients, or midyear, how should we think about the timing to seeing initial circulating biomarker data just given the potential to show proof-of-target engagement and delivery even albeit in small patient numbers? And then I guess just in terms of the C3 reprogram given that it seems like you're progressing through the cohorts. I guess how should we think about timing to initial data there and what you're looking to see for dose selection, such as a particular degree or level of knockdown and C3 as you think about dose selection for patients? Thanks.

Here, those are the questions I can't give you. I can't give you terribly straightforward guidance on any of those. I will say with C3 though, I do expect that we will that we will have some, at least top line data this year. I don't know when and I don't know what's going to be in it. We need to finish those escalation healthy volunteers before we, before we start to look for patients. I don't know how long it'll take to dose patients, in that in that cohort, so it's really too early to give any guidance there. But I do. I do truly, though, expect that we will have some data that we can talk about this year with C3, but that's atleast in healthy volunteers so far, is enrolling quite well. With RAGE and MUC. We haven't started dosing patients yet. That will be as you point out sometime in the middle of the year. And so similarly, it's a bit too, too early to guide when we might see some, when will I present some data. I expect that we'll see data this year. But I don't know when we'll have enough, to package up in something that will be digestible, by the outside. My hope is that sometime in the third quarter, we'll have a much better idea about that. And I can give you more, more specific guidance.

Got it. And then just a follow up on FSHD. Maybe just in terms of the decision to sort of wait for more of the chronic GLP talks data. I mean, I guess was there anything that you saw pre-clinically that influenced this decision? Or if you could just maybe elaborate on any sort of preclinical data points that maybe prompted this?

Yes, sure. So, the key driver of that this decision is what we have described already on the call is that this, we may not have clear evidence of PD effect or efficacy until end of Phase 2, really. So we felt like it was important to de risk that, that could be an I mean if you look back at the fulcrum study, and they're designed to be a longer study. So we really wanted to make sure that the tox profile would support such a longer study.

Got it. Thanks.

And our next question comes from Joel Beatty of Baird. Your line is open.

Hi, thanks for taking the questions. The first ones on the AAT program, thinking you had the discussions with FDA on the Phase 3 trial design. How might that trial design be different from Sequoia? And is there any possibility that ends up looking pretty similar to what's already in Sequoia?

Well, let's revisit Sequoia. I don't know if you remember that we changed the sign of the Sequoia. So the initial Sequoia adapted to trial design the how they objected to the registration study is no longer in play, we amended the protocol, we made it a specific dose finding study, we enroll for the patient in three dose range levels, or placebo. And it's a double blind study. We have a initial analysis looking at the seven C protein upto week 16 for the selection. And as we said in the call, we will have the last biopsy for the 40 patients in June or July of this year. So the data will be available late. And so the Phase 3 registration study will now be similar to Sequoia. In Sequoia we end up enrolling patients with F zero , so no fibrosis because that was irrelevant with regard to the seven C level of the protein for those selections, which that was the primary PD marker for the selection. So it's going to be different. Of course, we need to get into the details later when we have a meeting with the agency. But it's now going to be similar to the Sequoia study.

Yes, that's helpful. And then under two new lung programs entering the clinic midyear, what dose levels will you be testing and how do those dose levels compare to the dosing that was used in the previous ENaC study?

We’ve disclosed anything on starting this or either of those programs at this point. But it's good question and what your I assume you're getting at is, will we be? Do we expect to be using as much drug for these studies as we are for ENaC and I think the answer is we do not given the duration of the font looking for the time and interval between doses.

Got it. Thank you.

And our next question comes from Patrick Trucchio of HC Wainwright. Your line is open.

Thanks. Good afternoon. Just to follow up on HIF2 on the oncology platform, there's discussion in the prepared remarks around the program and that clear target engagement and demonstrated and that RNAi has a place in treating cancer, the improvements on existing constructs are needed to move forward. I'm wondering if you can elaborate on this commentary specifically give us an idea of when you could expect to have a next generation compound or compounds in the oncology platform ready for an IND or CTA enabling studies, what improvements specifically would be expected to be part of this program compared to HIF2 program? And would the target be the same or could we also have new targets as part of a broader oncology platform?

Sure, it's so first, I'll take these are part of that first, which is, which is targets. It will be a different target. As we mentioned, the great news for clear cell renal cell carcinoma patients is that is that there are now good alternatives that there are now good, good looking drugs that address the HIF2 alpha pathway. And so I certainly will make bets in other targets. There's a lot of other targets, I think that we could go after. Now with respect to timing, that's hard to know. I can't give you any guidance, certainly nothing this year. We were encouraged by the data, we are seeing knocked down, we can get into tumors, we can get knocked down in tumors, that's all good news. But I think we can do a bit better. I think we can, I think we can, we can get deeper knocked down. I think we can get more durable, knocked down. And so we're trying a number of different strategies to get there. And so and so it's still a bit early to give you too much to give you guidance on when we think we're back into the clinic. And also, and I've said this publicly before, at some point, it would make sense for us to find a good partner, for oncology, it's a difficult space. And, and it'd be great, at some point, if we will, if we can find a partner to work with on new targets, as well as on impossible delivery strategies. And so, we're still in the first few innings of this of this game. But the good news is, again, as I mentioned, I do believe we are on the board. I think we've got a good first. I think to mix my metaphors and we've got a good first step at this platform.

Yes, that's helpful. And just to follow up on ARCHES-2 program. First, can you discuss level of confidence that the program will not have the same setback as Lupin? And secondly, what would be considered homerun data in ARCHES-2, and when the data is reporting the first half of 2023? And then lastly, just how do we think about the clinical development path forward and mixed dyslipidemia in Phase 3 and potential commercial launch trajectory if the drugs approved?

All right. Let's see. With regard to the, to the ARCHES-2 program, we only see the first part of the equation that I kind of missing.

Oh, I think I was sufficient that we're going to have a very key safety profile and a very clear pattern of efficacy. I mean, we already have a lot of data, our Phase 1 study was over 100 patient with four different types of patients populations. And the results are very, very consistent. So I don't see any possibility for a drawback of any type there, so that the data is already strong enough. So I feel very comfortable confident about that. The Phase 2 study is going to read first quarter of this coming year, so we will have a full answer. But we're doing significant detail is working internally and with -- to really understand what is the best path forward for both molecules. When you think about mix dyslipidemia, we may talk about in more detail in the near future. But there's a lot of work going on to really understand who will be the patient population that might benefit from either or these two drugs. The therapeutic profile are clearly different. We believe that there are patient populations that will uniquely benefit from either of these two trials. But we are doing the work right now but looking at the biology, the specific biology and ask of the HDL biology, specifically, but also looking at databases and major clinical trials to understand where the residual risk for cardiovascular disease is in patient with mixed dyslipidemia. And so there is a lot of work that we want to finish by the end of this year. So we're ready for an end of Phase 2, we're ready to start to look at for companies and CRO, so on so forth to think about the major cardiovascular outcome trials. So I think we're in, like I said, we're doing a lot of work right now to be ready to receive that Phase 2 data, and have a plan to move forward going to the agency plan, our long term strategy, and our Phase 2.

So we expect to have a cardiometabolic day, later this year. And so I think, we’ll have, we can really kind of spread out and talk about plans and what we see at that point. But we're going to learn a lot with all these Phase 2 studies over the next year, plus. We’re dosed in an awful lot of patients different populations. And I think I think we're going to learn a lot about how ANG versus APO will address various populations. Having said that, at this point, the way we're thinking about these is as follows. For APOC3, we see a good, relatively near term opportunity in FCS population. We think we can get to market relatively quickly there. And become a commercial entity while we are doing, larger, longer studies to support the use of APOC3 against severe hypertriglyceridemia. We’re also as you know doing studies in mixed dyslipidemia. And so that gives us the optionality to maybe or maybe not do a very large outcomes trial for that, for that compound. On the ANG side, similar, we see an HoFH possible possibility, they're similar to the FCS opportunity where we can get to market relatively quickly. And while we are doing larger studies, we do believe that that, that a large outcome study would be interesting for ANG3, given what we've seen so far in the Phase 1study, and so that's our expectation at this point to go after the large dyslipidemia population with that, that that drug. Again, we'll learn a lot over the next year plus with these Phase 2s, and so and so some of those opinions may change a bit, but right now, that's what we're thinking.

Yes That's very helpful. Thanks.

You’re welcome.

And our next question comes from my Mayank Mamtani of B. Riley Securities.

Good afternoon team. Thanks for taking our questions and congrats on the manufacturing facility and the formation of . Actually, if I could go back on this, this topic that Chris and Javier you were commenting on continually, can you just summarize for us what is the opportunity you see, and sort of improving the perception of AG PDLT as a target? And sort of, obviously, in light of what we've seen with other modalities, and given the initial promise we had from the medallions work? Just as you're thinking about the cardiometabolic day would be helpful, I think, if you could comment on, where there might be some misunderstanding versus where maybe, maybe we need to learn something more. And then as a follow up question on the lung programs.

Yes. So as Javier said, our data were clear in our Phase 1/2 studies. We dosed a large number of patients, we saw consistent reductions in LDL, we saw, we saw a good safety profile, we saw consistent reductions in triglycerides. And so whatever other folks saw with their drugs, it's interesting to look at, I suppose, but I think our take home message is, is that our data were strong, and we expect that to continue now. We'll have an awful lot of data this time next year. But given the data we have so far, we feel as bullish as ever on that on that pathway, and on in on our drug.

Got it. And then as you start working on your Phase 1 studies for MUC and RAGE and deploy learnings from the ENaC program. And then, just the RAD study that I think is published at a conference about, how are you thinking about the dose level versus knock down? It looks like you're working with some lower doses here with the newer targets and but like, with the ENaC it was about 66% knocked down, but I think you're getting higher knock down with some of these newer targets. So can you just remind us like how, how much knockdown we need with these newer targets? And then, just maybe how far along you are with the chronic tox studies for these two new programs?

Yes. Sure. So we will be presenting data on both of those programs, MUC5AC and RAGE at ATS Conference starts next week. And you're right, we previously described for ENaC about 66% knocked down in the rat. And we are seeing better knock down than that, with both siRNA targeting MUC5AC and RAGE in, in rodents but also in, non-human primates. And we'll be showing some of those data. Either that story is, it's not only a matter of just lower dose levels have lower overall exposure, so the less frequent and dosing intervals, as Chris alluded to before, are really important, I think for both MUC and RAGE. Is there another piece of that question.

Chronic tox studies, how long have you gone, there in the preclinical model?

The Chronic tox has not yet started for either of those. We've completed the IND or CTA enabling talks. And that's complete for both MUC and RAGE. And, and let's be clear on that that's intentional. We want to see what the durability look like in humans before we do a chronic tox study in animals, just so we have, we have a good, we have a good idea about what sort of intervals we should be testing. Right? If we are dosing once a month, if we've seen durability, the last the last 30 days, that would suggest a certain kind of chronic tox study, if we're seeing durability the last two months or three months, that's another one. And so we'd like to get a flavor for what we're seeing before we start those studies.

Great. Thank you for that clarification. And then just one final question high, high level, has there any exploratory work done of delivering RNAi to the retina or broadly CNS? As oligonucleotides have been also deployed, have you guys done any work around that preclinical?

Yes, so we haven't talked about any other cell types that we are going after, internally. But you've been around us long enough to know that we are we are always looking for new cell types. And so we've not disclosed what our next cell type is yet.

Okay. Look forward to some of those disclosures and your pulmonary day later this month. Thanks for taking your questions.

Great. Thanks.

And our next question comes from Keay Nakae of Chardan. Your line is open.

Yes. Thank you for the question. With respect to HIF2 and going after additional oncology targets, I guess my question is, why why? Why do that as opposed to just on your last question, other targets, let's say outside deliver?

Yes, that's a great question. I don't mean to be flip, but we're, but when we can, we are, we are more of an -- company than or company. And I think we've got the bandwidth to both of those things. I think your point is a good one, we've got we've got really good leads and other cell types. And so if we were, if we were more bandwidth constrained, then one could argue that we should maybe slow walk the oncology a bit, because we've got, we've got really good exciting opportunities in other places, but I think we can do both. And also, as I said in the prepared remarks look, one of the reasons that we that the oncology program was important for us, is that it gave us gave us a chance to learn broadly how to deliver extrahepaticly. And I think that will, that will still be the case. So it makes sense strategically there. But the underlying point there is a strong one, oncology is difficult. And so it's, it's, it's we would not like to be solely an oncology company. That's, that's a risky endeavor. But it's something that I think we owe it to patients to it to investigate because I think we could do it. We've got a good, we've got a good first step, as I mentioned with the HIF2 alpha program. And I think that just with a little bit of tweaking, we might have something that can be usable across other tumor types.

Okay, thanks, Chris.

You’re welcome.

And our next question comes from Mani Foroohar of SVB Securities. Your line is open.

Hey guys thanks for taking the question. You've always focused on speed into the clinic is one of your core as one of your core competencies and sort of philosophy of the company. One of the challenges there is making sure that every target is appropriately vetted every market opportunity actually exists. So could you help us understand your rationale for why this opportunity for you in PNH. How you think about other company diseases were online and others with many times your resources and expertise in RNAi are facing real challenges? And then secondarily, are we ever going to see the further safety data that we saw into that safety signal that showed up in ENaC? Or do you intend to sort of hold that internally and not disclose in more detail? Thanks, guys.

So I'll let James handle the PNH question. Quickly on the ENaC. So we're still considering, a second, or we're still working on a second generation ENaC. And so I think until and unless we have that ready to go doesn't make much sense for us to focus on prior data. So we'll hold off until we see where that where the ENaC2 was going to go. James, you want to address PNH?

Yes, sure. So with regards to PNH, specifically, what interests us there is the data out of other companies with C3 inhibitions specifically, that there's only one C3 inhibitor that is out there, and that is approved, and really showed significant improvement, even compared to C5 inhibition in the PNH population. The issue with that C3 inhibitor is that it's a sub-q infusion that's given at high doses every other day, or I think almost daily in some circumstances. So that is limiting. An equivalent level of C3 inhibition with a single subcutaneous dose with C3 knockdown that last three months, I think, assuming it has the same inhibition of complement activity, and assuming you get the same changes in haemoglobin, I think that's pretty compelling. So that's, that's the argument for PNH.

Okay, that's helpful. And with the speed with which you're adding programs to the clinic. How should we be thinking about the tempo of OpEx maturation over the next couple of years? You commented on timing for, for CapEx being pushed out to next year? How do we think about the scaling of OpEx to be largely proportional to the size of these studies that you're enrolling? Will it be chunky around a lipid study just kind of give us a sense of how we should model that between now and say next two to three years?

Yes, so we gave guidance earlier in this year, we expect to update that at our at our call, two quarters from now. We only look forward really 12 months on that. And that forecaster we'll have more to come on that.

Okay, thanks, guys.

And I'm showing no further questions. I would now like to turn the call over to Chris Anzalone for closing remarks.

Thanks everyone for joining us on the call today, and we'll talk to you next quarter.

This concludes today's conference. You may now disconnect.