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 Vincent Anzalone, Vice President of Investor Relations for Arrowhead. Please go ahead Vince.

Thank you. Good afternoon everyone. Thank you for joining us today to discuss Arrowhead’s results for its fiscal 2021 third quarter ended June 30, 2021. 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 on our pipeline; and Ken Myszkowski, our Chief Financial Officer, who will give a review of the financials. In addition, James Hassard, our Chief Commercial Officer and Dr. James Hamilton, our Senior Vice President of Discovery and Translational Medicine, will be available during the Q&A session 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, the receipt of future milestone and licensing payments 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 Christy Anzalone, President and CEO of the company. Chris?

Thanks Vince. Good afternoon everyone and thank you for joining us today. The fiscal third quarter and the period since our last conference call has been incredibly busy for Arrowhead. We made important advances in several of our development programs. This includes discovery stage programs and early, mid, and later stage clinical programs. It also includes programs from existing partnerships as well as a new business development transaction. As a platform company, there are a few areas of critical importance where we focus our attention. First, we need to always push the boundaries of what is possible and make our TRiM platform better. Second, we need to expand the early-stage pipeline rapidly and efficiently with new clinical candidates, as this will be an important source of growth in the future. Third, we need to move our mid and later-stage pipeline programs through clinical studies, as it gets closer to our goal of bringing important new medicines to patients without adequate treatment options. And lastly, we need to selectively use partnering to expand the reach and maximize the value of our TRiM platform and bring in non-dilutive capital that helps to fund our internal development. I think we are doing well in all these areas. Let’s take a moment to briefly review some key events in the last quarter that are good examples of this. For our discovery and early-stage clinical pipeline, we had a very productive quarter. We completed discovery and optimization work on two new pulmonary programs and nominated them both as clinical candidates. They are now in the IND-enabling stage, which includes GLP toxicology studies and manufacturing of drug product for clinical studies. We have not yet disclosed the gene and disease targets, but we will be talking more about these programs later in the year. We also…

Thank you, Chris and good afternoon everyone. I want to give an update on our clinical studies and provide details on the design of a couple of our newest studies. First, I will discuss ARO-HIF2, which is designed to inhibit the production of HIF2α to treat clear cell renal cell carcinoma, or RCC. We were encouraged by the positive interim results from the first two cohorts of AROHIF21001, a Phase 1b dose-finding clinical study in 3 cohorts with advanced clear cell RCC. We are currently enrolling cohort 3, which is designed to include up to 10 patients who will receive a weekly IV infusion of 1050 milligrams of ARO-HIF2. The study is designed to evaluate the safety of ARO-HIF2, to determine the recommended Phase 2 dose and to assess pharmacokinetics and preliminary efficacy, based on RECIST and post-dose tumoral expression of HIF2-alpha and HIF associated genes. Patients will continue to receive weekly ARO-HIF2 indefinitely until they experience disease progression, have a complete response or they discontinue. Our intention is to share additional interim data from this study, including data from cohort 1, 2 and initial results from cohort 3 at an appropriate medical meeting in the future. We have not yet selected the intended meeting. The next program I want to detail is ARO-HSD, our investigational candidate for the potential treatment of alcohol and non-alcohol related liver disease. We think the interim data we presented at EASL was highly encouraging and in fact, our presentation was highlighted in the EASL Official Scientific Press Conference on NAFLD and NASH. It was exciting to see ALT levels drop significantly following just two doses of ARO-HSD. We expected a high level of target gene knockdown, because our TRiM system has been extraordinarily consistent across our different liver directed programs. But the improvement in…

Thank you, Javier and good afternoon everyone. As we reported today, our net loss for the quarter ended June 30, 2021 was $29.9 million or $0.29 per share based on 104.1 million fully diluted weighted average shares outstanding. This compares with net loss of $13.6 million, or $0.13 per share on 101.8 million fully diluted weighted average shares outstanding for the quarter ended June 30, 2020. Revenue for the quarter ended June 30, 2021 was $45.9 million compared to $27.4 million for the quarter ended June 30, 2020. Revenue in the current period primarily relates to the recognition of a portion of the $300 million upfront payment received under our collaboration agreement with Takeda as well as a $10 million option exercise payment received from Janssen for the ARO-JNJ1 program in May 2021. Revenue for the Takeda agreement will be recognized as we continue to work toward completing our performance obligations of managing clinical trials in process and certain manufacturing related services. The remaining $230 million of revenue associated with the Takeda collaboration is anticipated to be recognized over approximately 2 years. Any additional milestones achieved with our collaboration partners would be additive to this projection. Revenue in the prior period primarily related to the recognition of a portion of the milestones received from our license and collaboration agreements with Janssen. Our performance and revenue recognition under the Janssen agreement for HBV is substantially complete. Total operating expenses for the quarter ended June 30, 2021 were $77.8 million compared to $43.3 million for the quarter ended June 30, 2020. This increase is primarily due to increased candidate specific and discovery R&D costs as the company’s pipeline of clinical candidates has both increased and advanced. Net cash used by operating activities during the quarter ended June 30, 2021 was $29.6 million, compared with net cash used by operating activities of $33.4 million during the quarter ended June 30, 2020. The key driver of this change was the $10 million option exercise payment received from Janssen for ARO-JNJ1 program in May 2021. Excluding any potential milestones from our collaboration partners, we estimate our cash burn run-rate to be $50 million to $60 million per quarter. Turning to our balance sheet, our cash and investments totaled $644.7 million at June 30, 2021 compared to $453 million at September 30, 2020. An increase in our cash and investments was primarily due to the upfront payment received from Takeda offset by cash used by operating activities. In July, we also collected the $40 million upfront payment due under our recent collaboration with Horizon. Our common shares outstanding at June 30, 2021 were 104.2 million. With that brief overview, I will now turn the call back to Chris.

Thanks Ken. As I mentioned, we think we are making strong progress across the spectrum of activities required to be a successful platform company. We are innovating on the platform and pushing the bounds of what our TRiM technology can do. We are rapidly and efficiently feeding the early-stage pipeline with new candidates that may be engines of growth for Arrowhead in the future. We are moving our mid and later stage clinical programs progressively closer to our goal of bringing important new medicines to the patients who need them. And lastly, we are selectively and responsibly using partnering and business development when it makes sense to do so. This last quarter saw important and tangible progress in all these areas. Thanks again for joining us today. I would now like to open the call to your questions. Operator?

Thank you, Chris. Your first question comes from the line of Maury Raycroft from Jefferies. Your line is open.

Thanks for taking my questions and congrats on the progress. I was wondering for the bottleneck for the CPA filings for DUX4 and the two pulmonary candidates. Can you comment on whether this has anything to do with waiting for additional preclinical data from the ENaC?

It does not. It has to do with just finding slots of zeros. There is, we talked about this, I think a few conference calls ago that there is – that since the pandemic there has been a non-human primate shortage. And also these pulmonary studies are a bit more difficult to do, because there is not many CROs that do come in. So given all that we just – we have just had a bit of a bottleneck. And so we will get these done and just that we are going to get them done a quarter or two later than we had hoped.

Got it. Okay. And then also just wanted to check on if you are providing a status update on how that ENaC NHP studies going and you mentioned you may know more in the next few weeks and months, is it fair to assume that there could be an update on this and 4 to them? And in the next update, are you going to provide the some of the clinical data that you saw?

Yes. So I just don’t know. So with respect to the tox data, I just don’t know when we are going to have better clarity, we are not going to have the NDP data till towards the end of the year. And so that will be a black box until then. We haven’t yet that’s still ongoing and so there is just no data there yet. We don’t have final reports for the development piece of that. We are – that’s still ongoing. We just got an interim update, which caused us to press pause and now we are doing some other internal experiments. And so I can’t give you good guidance on when we are going to do something, we are working on it right now. And I think beyond that, it doesn’t make sense for us to talk about the clinical program until we have a better idea about where this is going to go and how quickly we might be able to get back on track if in fact, that’s going to work out.

Okay, that makes sense. And last question for me just Arrowhead to the tox data and the fact that the RCC looked good, at this point, do you have more insight into the relationship between knockdown and related tumor activity and how do you think actually could change at higher dose?

So we don’t – so with respect to the first question we don’t yet have anymore information. With respect to the second question, I don’t know fully, we are seeing this only – we are looking at this in real time and we haven’t seen data from the – from a higher dose yet. So we will see where that goes. What was encouraging to me at least was that it appears that we are on the board here, we are getting good target engagements, it appears we are getting knocked down. So now, let’s just see where this goes. I don’t – I would not expect a rapid sort of physiological response, if you will, with respect to tumor shrinkage and such through this pathway that may take a bit longer. So, the fact that we are seeing right now some knockdown suggest to us that our platform is working and so now we just need to see how that’s going to go going forward.

Okay, that’s helpful. Thanks for taking my questions and I will hop back in the queue.

Sure. Thanks, Maury.

Thank you. Your next question comes from the line of – from Alethia Young of Cantor. Your line is open.

Hi, this is on for Alethia and thank you for taking our questions. We are wondering if you could share more on your DUX4 program and how it compares to competitors? And also, if there is any read through from the Phase 2b results for Losmapimod, which missed on the primary endpoint in change with DUX4?

Yes. So I will let James comment on that. I don’t – well, I will let him comment about I don’t know that there is read through with the other one, because it’s different. It’s different compound entirely, of course, but James?

Sure. Maybe I will take the first question first about the how we compare with the competing programs. There is not a whole lot out there. With regards to the other oligo programs, the targeted anti-sense programs are all preclinical and there is really not much data available. And so the primary difference would be the way that we target the muscle cells that we use a peptide targeting ligand versus their antibody or antibody fragment approach. So that’s – I think that’s the main difference as far as comparing and there is really no way to compare efficacy or knockdown levels as the other competing programs have not shared any data at this point. And then the other question was around the Fulcrum read-through set right. Yes, it’s tough to say. I mean, it’s a very different compound different mechanism. I think they did highlight the challenges associated with a biopsy study in this population. And with this specific target, where there is this sort of stochastic expression of the target that maybe difficult to catch or to monitor, if you will, with biopsy. And so we will look at downstream gene expression, but we will likely also look at other parameters that might help us select a dose for later stage clinical studies.

Yes.

In this study, I wanted to add another comment about this data, which I think that despite the biomarkers, the clinical data in semester was positive. So I think the target still is in a good place. Because if you look at the PLL and the physical function there is a number of products that were statistically significant, we don’t know how clinically relevant dose changes is. And we are looking at that to try to see if some of those changes correspond with the minimal relevant changes and that I think will help us to understand this. So, I think there is a mix of results here despite the biomarker now being positive. I mean, it’s clinical sciences of potential improvement in this patient population, which I think is excellent for the pathway.

Okay, that’s helpful. Thank you.

Thank you.

Thank you. Your next question comes from the line of Esther Rajavelu from UBS. Your line is open.

Hey, thank you for taking my question. I have two. One on ENaC, so it’s historically been a tough target, but what are some takeaways from the tox signals that you are seeing? Is it specific to the lung or is there evidence of exposure in other tissues? And what would your considerations be if you find that the tox is limited to the lung?

So, let me just say two words and I will hand it over to James on this. The tox that we saw whether we heard about, again, we haven’t had a final report on this rat study. So we had a limited data, but what we understand is that it was local lung inflammation. We don’t see – we didn’t see broader issues. We don’t know if that’s species specific, because as I said, we don’t have the NHP data yet. We don’t know if it is sequence specific or is target specific. There is – we are really just starting to get into this.

What was the other part of the question?

The other part of the question was, if you sort of consistently see that the toxes when you get the NHD data, if you see the toxes limited to the lung, would it – I mean, how would you interpret that, is it specific – would it – is that a good thing, because the drug is getting to the lung and you just have to find another target that works maybe in a different or do you – or would you have to go back and change the chemistry?

Well, if the tox being limited to the lung, as Chris has stated is not surprising. I mean the systemic bioavailability with inhalational oligos is not that great. So it’s not unexpected that we would only see tox in the lung. I think it depends on what we would see in the final results from the rat and then the NHP study in terms of what the toxicity is and at what dose levels and dose frequencies there, again, depending on the results and we don’t have these results, yet, there maybe an opportunity to resume the study as is or to amend take a look at different dose levels, different dose intervals.

Right. And following to that, remember that we dose this, we can dose this reasonably high, but also we dose it relatively frequently. And so to James’ point or as he alludes, if we are – if this appears to be clean in the NHPs, it could be that we have an opportunity just to space out the dosage is a bit more. That’s all speculation. Let’s see where the data come in and we go from there.

Got it. Thank you. And then on AAT, are you still on track to revisit the registrational trial design with the FDA and I think you said in the third quarter, late summer or thereafter?

Javier?

And you say the initiation of the Phase 3 study?

Yes.

Part of the introduction, yes. So as you probably know, we have been granted with breakthrough designation about a week or 2 weeks ago. We are already working on the briefing document to engage in the first what is called multidisciplinary meeting, yes, in the Q3-Q4 timeframe.

Thank you.

Thank you.

Thank you. Your next question comes from the line of Joel Beatty from Baird. Your line is open.

Hi, congrats on the progress. Couple of questions on the HIF2a program, the first is with the dose response in reduction of HIF2a seen in among those two doses in that study. And then I have a follow-up.

The dose response between the first two cohorts, yes, I think we are still in the process of dose escalating and analyzing all the data from the second cohort. A lot of those patients are still on drugs. So, I think it’s too early for us to really give a clear answer on dose response.

And a further complicating factor is that I may get these numbers wrong. So correct me if I’m wrong, we had of 17 individuals, I think we only had usable biopsy material from 9 of them. And so it may be difficult to know if we haven’t just sponsored at this point. The only think I will add is that we did knockdown in both doses.

And in the press release we were just giving an overall top line on this. And so our intent, we said this in the prepared remarks is to present a more full dataset at an appropriate medical meeting, which will include the top dose level as well. So stay tuned on that.

Yes, okay. That all makes sense and it is helpful. Sorry, just one follow-up on the – you mentioned there is one responder with a fair response, are you able to share anything about the HIF2a reduction that was seen in the patients?

Yes, not at this time. I think we can share that when we present the full dataset at an upcoming medical meeting.

Great. Thank you so much.

Thanks.

Thank you. Your next question comes from the line of Salveen Richter from Goldman Sachs Group. Sir, your line is open.

Thanks for taking our question. This is Sonia on for Salveen. We were just wondering like beyond the pulmonary target and the muscle target, what other extra hepatic tissues would you be looking to go into on the forward?

So, we have active programs in a number of areas. We have not disclosed other areas that the other effort that we are working on. So yes, just facing on that – look, we have mentioned in the past though the CNS clearly is a target rich environments. So, it’s a place we want to go at some point. We are not there yet, but there is a number of tissue types that we are looking at.

Thanks.

Sure.

Thank you. Your next question comes from the line of Luca Issi from Royal Bank of Canada. Your line is open.

Great. Thanks for taking the question. This is Lisa on for Luca. Just one on A1AT, can you give us some directional color here on more with the ongoing dialogue with the FDA, now that you have Phase 2 designation, there maybe a scenario where the data from the 202 study and the first 36 patients from sequoia will be sufficient for accelerated approval? And I also have a follow-up on the ENaC.

This is Javier. Yes, we are thinking about all of those options. Right now, we will need to focus on the first interaction. And typically, this first interaction as I say is a multidisciplinary meeting. We will touch upon different aspects of the filing process, discuss the Phase 3 study design, the approval endpoint, and the time to filing is going to be critical, but it’s now a one-stop conversation, it’s a process. So, it’s a good thought and we will of course entertain that thinking and that potential step forward.

And we have had really so far limited interactions with the FDA and particularly with the current division. But our interactions have been quite positive and collaborative. They clearly appreciate that this is an unmet medical need and I think that they are really interested in working with us to get this to patients who need us. And so we haven’t had, so we are really excited to have this breakthrough designation. So, we can sit down and have these more in-depth discussions.

And to your point, breakthrough designation essentially opens the path to an approval based on the surrogate likely to translate into clinical benefit. And that’s precisely what we will discuss. The next time around, there was a significant component of the breakthrough resignation briefing document. So, yes, we are going to talk about this throughout the process.

Great. That’s helpful. And then just one on ENaC, just wondering if you can talk about the doses at which you are seeing the tox result in rats and how those doses scale into humans? Just trying to figure out here whether the signal of – the tox signal seen in rats was seen at maybe super therapeutic doses or at doses that scale within the 40 to 180 mg range that are being tested in humans? Thanks.

Sure. And I appreciate the question. But look, it is – it has been our policy not to talk about tox data, in particular, because we don’t even have you have a final report here. We just – we have just been given a small synopsis about part of a rat study. We don’t even know anything about the NHP. So, we are unable to give you any more color on that at this point.

Okay, got it. Thanks for taking the questions.

Sure.

Thank you. Your next question comes from the line of Patrick Trucchio from HC Wainwright. Your line is open.

Alright. Thanks. Good evening, just a couple of follow-up questions on the C3 program. Well, first, can you discuss what if any potential vendors are targeting C3 rather than C5? And secondly, do you know which indication or indications of the C3 program would initially focus on, when that clinical development could begin? And is this a program you would bring into clinical development on your own or would you seek a collaboration partner?

I will answer the last of those questions and then I will hand the rest over to James. So, we do not have plans to seek a partner right now for this program. If you look that may change in the future, but right now we are having to take this forward. This is directly in our wheelhouse in terms of preclinical development. This is a directed construct. We feel good about going to clinic. And so let’s see what the data look like. And then we can make a decision on partner versus non-partner at some point in the future. James?

Yes, sure. I will take the first part of the question that I think was about C3 versus C5. So, C3 in the complement cascade is a central node that is involved in all three different components of that pathway, the lectin, the alternative and the classical pathways. So, if you can inhibit C3, you can really take out everything that’s downstream of C3 and so the effects should be broadly applicable to various complement mediated diseases. Now, specifically to two interesting indications PNH and C3 glomerulopathy, that Chris mentioned during the earlier remarks. PNH is a disease that’s been reasonably well treated with C5 inhibition. However, there is a component of that population that is refractory to treatment, due to extravascular hemolysis. That’s primarily driven by C3. So, that residual population with the residual anemia, that’s refractory to C5 inhibition, could be specifically treated with – potentially treated with C3 inhibition. There is another population, that the C3 glomerulopathy patients where their disease is really driven by excess C3 activity in deposition of C3 fragments in the glomerular. So, that’s really a C3 driven disease. Beyond those, there are other conditions that are where the disease is, complement mediated, and maybe not as specific to C3 as those other two conditions, complement mediated. And we think that C3 inhibition may have applicability in those other complement mediated diseases. So, I think that covers maybe both the first and the second question about C3 versus C5, as well as the other indications.

And one other question was about when we can enter clinical development?

By the end of the year. So, we will be filing CTA by the end of the year.

Got it, that’s helpful. And then just a follow-up on the gout program, can you tell us where ARO-DUX would fit from a gout treatment paradigm, and the potential cadence of the $660 million in potential milestones from price and so maybe something you could comment, when the program could be expect it to enter a clinical development?

We can’t say anything about that, about any of those actually. So the – so we did not split out what the – how the $660 million of potential milestone payments could be achieved. With respect to how this could fit into a clinical paradigm, this is one of the reasons we chose Horizon as a partner. This is their business and we work closely with them. But ultimately, this is their decision. And so I don’t want to step on their toes and tell you something that we believe when this is really going to be their business. And with respect to what you asked and when they are going to begin the clinic, we don’t know the answer to that. This is still an early program. We are just working out right now. And so it’s, we still have ways to go.

Got it. That’s helpful. Thank you very much.

You’re welcome.

Thank you. Your next question comes from the line of Ted Tenthoff from Piper Sandler. Your line is open.

Thank you everyone. And I just wanted to get a sense a little bit more on the new pulmonary targets. What are our gating factors, and is there anything you expect to learn from the ENaC program that could impact those programs come into the clinic. Thank you very much.

Yes. So, that’s a good question Ted. I don’t know the answer to that. It’s still just too early. We don’t know what’s going on with what happened in those rats in the ENaC program. And so until we have more information, I just don’t know how that might read on future programs. I can’t go, it slowed us down. We – this is still we think a big opportunity for us. And we are still moving as quickly as we can. We are excited about these two new programs. We haven’t talked about the gene targets. We haven’t talked about the disease areas. I expect that we will maybe later this year. We were disappointed that we couldn’t get the slots that we wanted to move this into the clinic this year. But that’s just the way the world turns right now. And so we look forward to getting this in the clinic in the first half of next year. I will say that what we think we have seen, because again, I have always seen small data from that rat study. But what we have seen there has caused us to do a bit more work while we are waiting just internally on chronic studies. These are non-GLP talks, again these are just so. So, we understand a bit more internally on the other programs.

And with respect to with the patients who have already been dosed. How do we anticipate hearing about that data? I know you are not dosing anyone going forward. But is that going to be a doing whether it’s going to be informative? And is that something you would share publicly?

Yes. And again, I am sorry. I can’t give you a definitive answer on that. Just because we don’t know, what’s going to happen with that program. And if we can restart it, when we don’t know, when we can restart it. So, until we have more information, we just would rather not give any sort of guidance one way or the other.

I really understand. Yes. Totally understand. Awesome. Chris, thanks so much for the update and really a lot of great progress this year. So, I am excited for back half.

Thank you, Ted.

Thank you. Your next question comes from the line of Keay Nakae from Chardan. Your line is open.

Hi, thanks. Yes. Chris, just following up on the new programs, so what are the similarities between the construct for those versus ENaC? I mean, obviously, you are going to have a different sequence for the targeted June. But are you using the same targeting ligand. And so help us try to better understand what the potential read across of risk is from the ENaC tox?

Right. So, we are using the same formula again, as you said different sequences. I would expect that we will be using less material in the next two, because at least in animal studies, they both appear to be more potent than ARO-ENaC. Is that important, I don’t know. But I believe that as well, I know, it’s the case for animal studies. And we will see that translates into humans. And so if again, until we have more data, it’s just too early to speculate on how that what we saw in the chronic tox, interacts, may translate to other sequences.

Okay, thanks for that. And then just for James, the biopsies that you received and the fact that some of them weren’t used, but can you just further characterize that and how we think about the risks there going forward of not being able to get the data to do your assessments?

James?

Yes. So far maybe I will make one comment about the study design the protocol allows us to enroll up to a sufficient number of patients to get enough biopsies that we think are adequate – paired biopsies to make to do our analyses. And as was described in the press release, the biopsy samples are not always analyzable. But so far in the first and second cohort, and then and so far in the third as well, we have been able to get enough biopsy samples to do the work that we need to.

Okay. Thanks.

Yes. Thank you.

Your next question comes from the line of Mayank Mamtani from B. Riley. Your line is open.

Hi, good afternoon. This is Sahil Kazmi on for Mayank. Thanks for taking our questions. Maybe a brief one on HIF2, could you provide any color on kind of how the enrollments been tracking maybe in the context of the program and maybe approval or just increased awareness on VHL disease associated with RCC?

Yes. Enrollment has been actually really good in that program throughout. We have not seen any challenges with enrollment and all the slots have filled very rapidly. And so I know that the Merck study is ongoing, but it has not detracted from enrollment into this study.

Okay. And then maybe on HBV, do you have any insight into kind of what forum J&J might present for the 24-week of treatment data from reads and/or any high level thoughts on kind of what we can incrementally learn from that study?

Boy, no. I can’t give any guidance on that. Look, we look forward to seeing those data, but I don’t know what their plans are to be honest about where that could be presented.

Got it. Thanks for taking my questions and congrats on the quarter.

Thank you.

Thank you. Your next question comes from the line of Mani Foroohar from SVB Leerink. Your line is open.

Hi, good afternoon. This is Rick on line for Mani. Thanks for taking our questions just two from us. So first, for HIF2, could you speak to some of the variability of knock down seen with data? I know there are a lot of data sets on value in tumors. So, some of this variability just due to the heterogeneity of tumors in general or it was something that could potentially be resolved by looking at higher doses or either earlier lines of patients?

Yes. I think that you hit the nail on the head. I mean I think there is that heterogeneity of expression in the tumors and across from patient to patient. And also heterogeneity in between paired biopsies, you are not necessarily getting into the same area of the tumor. So, heterogeneity is definitely an issue and probably explains a good component of the variability.

Alright. Got it. Alright. Thanks a lot. And one of the much more broad question, so just in general, I would approach to extrahepatic deliveries needs to be focused around integrates with specific ligand conjugates. Can you maybe speak to why these are so favorable to target other class of molecules? And if the company is currently exploring another targeting strategies pre-clinically.

Yes. So, I will let James to go, has also been budgeted broadly. We are not an integrin targeting company. We are an R&D company. And so we tend to use what works best. And we are agnostic. We have done work with antibodies with antibody fragments, with peptides, with modules and such. And so, we just, we have ideas about what might work best, but ultimately, the data will tell us and so it just so happened that we have that, that interment based targeting has been quite good for us. So James?

I will go with that, that we don’t report works. And we went with integrin receptor ligen in pairs, not because that was our area of expertise, but because that was what was looking the best. And we continue. We have historically evaluated multiple different receptor ligand pairs and continue to do so. And I think we will continue to go with what works regardless of what the modality is, if it’s an antibody or a small molecule or something else.

Great, I appreciate all the detail.

Yes. Thanks very much.

Thank you. There are no other questions on the queue. I will now turn the call over back to Chris. Please go ahead.

Thank you all for joining us today and I hope you have a nice evening and afternoon.

This concludes today’s conference call. Thank you for participating. You may now disconnect.