Arrowhead Pharmaceuticals, Inc. (ARWR) Earnings Call Transcript & Summary

Good afternoon, and welcome to Part 2 of the 2-part KOL Webinar series hosted by Arrowhead Pharmaceuticals. [Operator Instructions] As a reminder, this conference is being recorded, and a replay will be made available on the Arrowhead website following the event. I would now like to turn the call over to your host, Vince Anzalone, Vice President of Investor Relations at Arrowhead Pharmaceuticals. Please go ahead, sir.

Thank you, Sara, and thanks, everybody, for joining us again today. And for those that missed it, we had another webinar yesterday to go over ARO-APOC3 and today, we'll be talking about ARO-ANG3. So next slide, please. Next slide, please. Okay. Just a reminder, we will be making forward-looking statements today. So please refer to the risk factors in our SEC filings. Next slide, please. We have a really good panel today, and we're very happy to have, again, Dr. Ira Goldberg from the New York University Grossman School of Medicine, where he is the Clarissa and Edgar Bronfman Professor and the Director of the Division of Endocrinology, Diabetes and Metabolism. Thank you so much, Ira, for joining us today. And then from the company, we have our President and CEO, Chris Anzalone; our Chief Medical Officer, Javier San Martin; and our Chief Commercial Officer, Jim Hassard. Next slide, please. So this is very similar to the format and the agenda that we had yesterday. Jim will be giving a brief overview of the market opportunity for ARO -- I'm sorry, for ARO-ANG3 in mixed dyslipidemia. Dr. Goldberg will then talk about ANGPTL3 as a therapeutic target to treat mixed hyperlipidemia or mixed dyslipidemia. Javier will then talk about the ARO-ANG3 clinical development as well as some data that we presented at AHA on Friday. And then Chris will give a wrap-up and a summary and why we think it's an important program for the company, and then we will have a short amount of time for questions at the end. Next slide, please. So I'm not going to go over all of this again, but Arrowhead does have a very broad pipeline across therapeutic area and across target tissue. Today and yesterday, we're focusing on the top, which is our cardiometabolic programs. And between the 3, we think we're hitting some pretty major residual risk factors for cardiovascular disease. And that's triglycerides, persistently elevated LDL-cholesterol and then in partnership with Amgen, lipoprotein(a) or Lp(a). Next slide, please. And I'll turn it over to Jim to -- who will speak about the market opportunity. Jim?

Thank you, Vince. So let's talk about the impact of cardiovascular disease in the United States and the residual risk that remains despite the fact that there are lipid-lowering drugs available within the U.S. So there are 600,000 deaths estimated per year within the United States. Costing a projected $1.1 trillion projected in 2035. And despite the fact that statins currently reduce the risk of cardiovascular disease by 20% to 40% presumably by lowering LDL, there is a 26% increase in the rate of major cardiovascular events in patients with cardiovascular disease on statins, if those patients have a triglyceride level above 150 milligrams per deciliter. So this raises the concept then of mixed dyslipidemia. Next slide, please. So again, within the United States, among patients that are currently on statins within the primary prevention space, there are an estimated 10 million to 12 million patients that do not achieve both their LDL and triglyceride lowering goals. Among patients who have had an event, in other words, secondary prevention patients, there are an estimated 4 million to 8 million patients who, again, despite the fact that they are being treated with statins and other interventions, do not reach their goals. So this raises the opportunity for a single product like ARO-ANG3 that could actually, again, address both LDL and triglycerides. Believe it or not, these are patients -- these are the numbers among patients who are on statins currently. There are also an estimated 32 million patients within the United States that are not on a statin and not reaching both their LDL or triglyceride lowering goal. Next slide. So at Arrowhead, what we're looking for are unmet needs, spaces where there are currently patients with unaddressed diseases. And if you look at that far left of this slide, you can see that the clinicians have a number of interventions in order to, again, address hypercholesterolemia, in other words, high LDL. So statins, PCSK9s, et cetera. So those are certainly met needs on that side. Yesterday, we talked about, on the other side of the landscape, on the right side here, we talked about ARO-APOC3 and the possibility that the white space that we have there as an opportunity for patients where there are, again, few interventions that clinicians have that can be effective, especially in rare diseases like familial chylomicronemia syndrome. Fibrates, Vascepa are available for severe hypertriglyceridemia, but again, severe unmet needs exist there. This leaves us again with an unmet need in the middle, which is mixed dyslipidemia. Although there are combinations like ezetimibe plus fibrates that are approved by the FDA, there is no single agent that is actually approved for mixed dyslipidemia. This is the role that we hope ARO-ANG3 is -- in the future would be able to play. And again, between efficacy and also the opportunity for patient compliance, we do feel that there are attributes of ARO-ANG3 that can really fulfill an unmet need in this space. And so without further ado, I'd like to hand it over to, again, Dr. Ira Goldberg, who would like to talk to us about the opportunity for ANGPTL3 as a therapeutic target in mixed dyslipidemia. Dr. Goldberg?

So thanks, Jim. Next slide. So let me tell you a little bit about my background. So I'm the Division Director of Endocrinology at NYU about 6 or 7 years ago. Prior to that, I had been at Columbia University for several decades where I actually ran the lipid and preventive cardiology section at Columbia. So I've spent probably the last 30 years dealing with lipoprotein disorders. Most of the patients with severe hypertriglyceridemia in the New York area often get preferred to me, along with some other genetic issues. And we have a large group at NYU that includes endocrinology and preventive cardiology, and we meet together every Thursday to go over these things. It's exciting for me that right now, we have 2 new really exciting new targets that I suspect within the next few years are going to make a major impact in helping us take care of patients. Next slide. So this is what I'm going to do. I'm going to tell you a little bit about lipid disorders. I know you heard from my colleague Christie Ballantyne yesterday, but I'll probably slant it a little bit more to the way I think about things. I'll tell you a little bit about atherogenic lipoproteins that are not LDL. And then I'll tell you a little bit about how this target got discovered ANGPTL3 and a little bit how it compares to what you heard yesterday about APOC3. ANGPTL3 will also lower HDL, and I'll tell you a little bit about what we think about HDL currently now. And then I'm going to end up with a little bit about a patient who might benefit from this kind of therapy. And then I'll be around for the discussion questions at the end. Next slide. So lipoproteins in the bloodstream really come from 2 different sources. One is the fat that you eat. And that fats comes in, gets reassembled in your gut. Comes into your bloodstream in a big particle called chylomicron, which is a big floating fat droplet. That particle hits an enzyme called lipoprotein lipase shown here as LPL that breaks apart the triglyceride. If you're a chemist, you know that's an esterase and it takes the fatty acid away from its glycerol backbone and creates a particle that we think is the remnant. I'll tell you a little bit about that. And the remnant is cleared from the blood stream and the fatty acids go to tissues. The second major source of lipoprotein, lipids in your bloodstream is what comes out of the liver. And it comes out as a particle called VLDL, full of triglycerides, and that's the precursor particle that eventually makes the so-called atherogenic LDL. Again, it hits the same enzyme, lipoprotein lipase, the lipid triglyceride comes out but the cholesterol is retained in the particle. And that's why the LDL is a cholesterol particle and the VLDL really a triglyceride particle. Next slide. So there are rare patients that present with super high levels of triglyceride. So if you look at this patient's blood, it actually looks like cream. So cream is about 8% fat. And this person's triglyceride in the blood is about 8,000 milligrams per deciliter. And the real problem with these kinds of patients is they develop a condition called pancreatitis, inflammation of the pancreas, which is associated with very high triglycerides. These are really hard patients to take care of, really hard to treat. Some of them have genetic defects, and a lot of them also have lesser genetic defects but have diabetes. Next slide. So fasting triglycerides over 1,000 occur in rare genetic -- rare genetic defects. In this genetic analysis by my colleague, Rob Hegele up in London, Ontario, he's the triglyceride geneticist across the country. And these are rare patients and these rare patients have defects in a number of enzymes, including the lipoprotein lipase enzyme that I just mentioned. But high triglycerides are really common, almost 30% of the entire population has high triglyceride levels. Some of these people or many of these people have minor genetic mutations. And those minor genetic mutations are amplified when they have a dietary issue and the dietary issue or a lifestyle issue or medical issue is that they could have diabetes. They could have drugs that raise triglycerides, including estrogens, data blockers, many antihypertensives and these people probably are at increased risk. The people with the heterozygous mutations in the triglyceride degrading enzymes by GWAS genetic analysis, those people always have increased risk. Even if they don't have triglycerides of 1,000, but they have triglycerides over the norm, this 30% of patients. Next slide. So the relationship of triglycerides and cardiovascular diseases vexed clinicians and scientists of vascular biology for decades. So this paper came out. Actually, when I was a medical student, it was written by Joe Goldstein, who won the Nobel Prize for work on the LDL receptor. And when he was a postdoc, he wrote this paper, kind of highlighting that hypertriglyceridemia was a really common observation in people with coronary disease and made this comment that hypertriglyceridemia might be as important as cholesterol. And then he wasted the next 40 years or so studying cholesterol. And so he never really solved the relationship of triglycerides and cardiovascular disease. Next slide. So this is a cartoon from a review that I did with Bob Eckel, who is the current American Diabetes President and AHA President a few years ago and Ruth McPherson who is the geneticist up in Canada. And this is what people think that the triglyceride particles by themselves are not atherogenic. But after they hit the lipase enzyme and they start to get degraded, they become these remnants that actually could be atherogenic. Some people actually think it's the lipids that come off the particles that then damage endothelial cells. The truth is we don't really know why this relationship happens, but we do know that higher triglycerides tell us somebody has had increased risk. Next slide. So this is what the lipase enzyme does. It breaks apart this triglyceride molecule, takes off the fatty acids 1, 2, 3, and enables them to go into tissues. And it really is the controller of circulating lipid levels. Next slide. Okay. So how is this regulated? So like most enzyme systems, it has a complicated regulatory process that includes activators and inhibitors and it also binds the endothelial cells. So it's important to have a binding site. There's also a protein called A5 that probably increases the ability of the triglyceride particles to home to the vessel wall. But it has a couple of inhibitors which might be good to get rid of. If we can get rid of these inhibitors, we can make the enzyme work better and get rid of triglycerides. You heard about APOC3 yesterday, so I won't discuss it further. And I'll tell you a little bit about how this target ANGPTL3 came about. Next slide. So every once in a while, I get referred to me a patient, and they send me the patient because they have a cholesterol level of 30 in the bloodstream or 40 or 50 and they also have fatty liver. Because if your liver cannot take lipids and excrete them into circulating lipoproteins, then what happens is you get in the liver. So instead of the lipid being in the blood, it happens to be in the bloodstream. My little square there is a little higher than it should have been, but it was supposed to circle the name Gus Schonfeld just below where it is there. So Gus Schonfeld was the Chairman of the Department of Medicine at Wash U. And about 25 years ago, he described a family in St. Louis. And that family had very low levels of circulating VLDL, triglycerides, very low levels of LDL and very low levels of HDL and no heart disease and also no fatty liver. And then it took decades to figure out what was different about this patient and why this particular family in St. Louis was different than most of the people that had been seen that had low levels of LDL and also fatty liver. This genetic analysis then came out now 10 years ago, and said, what these people have is they have a defect in a protein called ANGPTL3 or angiopoietin-like protein 3. Next slide. So what does this protein do? So you heard a little bit about how C3 works yesterday. What people think the ANGPTL3 does is that it binds directly to the lipoprotein lipase molecule, so this schematic drawing came out, oh, somewhat less than 6 months ago. And it was done by a group at UCLA. And what they came up with was that ANGPTL proteins and the protein they happen to use as ANGPTL4, but it's probably 3 works in the same way that this protein binds to this area on the C terminal, where you see the antibody binding. And when it does that, it unravels the LPL protein and makes it inactive. And ANGPTL3 circulates in the bloodstream. ANGPTL4 is actually specifically in adipose tissue. And what these investigators did is they block the inactivation by using a specific monoclonal antibody that binds to lipoprotein lipase. But instead of giving that monoclonal antibody, which should be kind of a weird thing to do, what we can now do is just get rid of the ANGPTL3, and that's what you're going to hear about. Next slide. So what's the clinical data? So the way you could get rid of a protein that's made in the liver is several different ways. You're going to hear about a silencing RNA, but you could also get rid of it using monoclonal antibodies and both kinds of approaches have been used. And in the last 2 to 3 years, a whole series of papers in New England Journal, both looking at triglyceride reduction and LDL reduction by lowering ANGPTL3. And the public studies are mostly with monoclonal antibody and some with ASO. And you'll hear what the silencing RNA does in a couple of minutes. But this approach is remarkable. So in patients with really high triglycerides, they go down like 70%, patients with very high cholesterol, including a paper that just came out this week, cholesterol or LDL levels are markedly reduced also. Better than 40%, almost 50%. Next slide. So one of the questions we've asked is how good is ANGPTL3 versus what you heard yesterday, lowering APOC3. And it's kind of hard to do that experiment in people. And so what we've done in the lab is said, let's go back, let's take a group of animals and let's knock down either the C3 or the ANGPTL3 using both the sRNA that actually was made by Arrowhead. And as shown on the sort of upper left panel, the -- about 70% reduction in triglycerides was almost identical using either approach. The thing that was not identical is that LDL cholesterol also seems to come down in the mice, and it doesn't come down with the C3. It's hard to measure the LDL because mice have very low LDL levels. The other thing different about the ANGPTL3 approach is that HDL cholesterol, just like was seen in humans, also comes down, and it doesn't really come down with the C3 therapy. Next slide. We also used this antisense in patients who were lipoprotein lipase deficient. So I told you that one of the actions of ANGPTL3 is to inhibit lipoprotein lipase. So you might expect that if you had a person or a mouse and they didn't express the lipoprotein lipase, it wouldn't matter if you took out the inhibitor. And in fact, that's what we thought. But it turns out not to be true that the ANGPTL3 siRNA also lowered triglyceride at least in mice who were lipoprotein lipase deficient and actually worked as well as APOC3. So there appears to be another pathway that ANGPDL3 uses to get rid of triglycerides other than the LPL pathway. And I don't know what it is, and that's hopefully what we'll find out at least in the laboratory. Next slide. So the last thing is I told you, HDL goes down. So HDL, if you're an investigator, is really interesting now, if you're a clinician, may be less interesting because the thought was that HDL circulates, hits macrophages like this and a cholesterol falls out of the macrophage and is picked up by the HDL, so-called reverse cholesterol transport. Next slide. However, this idea that the HDL really was so protective against cardiovasculars didn't fit with the genetics that we knew. There are a whole slew of diseases that have really low HDL. Some of them have cardiovascular disease, but a lot of them don't. And then there's some diseases or genetic problems that lead to very high HDL levels. And those high HDLs don't look like they're protective. And then large population studies have found that several of the things that regulate HDL, including an enzyme called endothelial cell lipase, which is the enzyme that actually probably causes the HDL reduction with ANGPTL3 knockdown, it doesn't track at all with cardiovascular disease. So people are not really sure what HDL does, and they're not so sure anymore about the relationship of HDL in cardiovascular disease. So I think the drop in HDL with this kind of therapy is not likely to be clinically important. Next slide. So who could use this therapy? This is a typical patient. I probably see this patient every week. 60-year-old man, has cardiac disease. He's a little bit overweight. He has some diabetes, and he has a mixed lipidemia. His triglycerides are up, and his LDL is up. This is the traditional pattern in somebody with diabetes, by the way, that the triglycerides tend to be up. It's called diabetic dyslipidemia. Next slide. So what do you do? Well, you put them on a high-dose statin like rosuvastatin 40, and his LDL will go from 185, maybe to 85, go down 50%, maybe 60%. And then he'll say, is that good enough? And it probably isn't where national guidelines are to reduce LDL below 70 and European guidelines to lower it even more to try to reduce cardiovascular risk. So you can put him on ezetimibe. He'll drop another 15% maybe. If you're lucky, his insurance may give you PCSK9 and it can drop it also. But neither of those approaches would really drop his triglycerides, which is probably another risk for him. But ANGPTL3 inhibition likely will. And this kind of patient after his statin, it may be in the future that ANGPTL3 inhibition will be his next therapy. Next slide. So this is the take-home. High triglycerides occur, occurs commonly in the population. Triglycerides can get lowered by ANGPTL3 or APOC3, but the ANGPTL3 also reduces LDL, and it reduces HDL. But probably the HDL changes are not really clinically important. The human genetics suggest that ANGPTL3 leads to a really good non-atherogenic lipoprotein profile. And more than that, other things that drop, liver production of lipoproteins that lead to steatosis or fatty liver are unlikely to happen with this particular therapy. And I'll turn this over to the next speaker, Javier.

Thank you, Dr. Goldberg. Next slide, please. Dr. Goldberg already explained very well the underlying pathophysiology of dyslipidemia and the role of ANGPTL3. Essentially, ANGPTL3 is an inhibitor of lipoprotein lipase and endothelial lipase. So when a condition is related to the excess of a given protein, inhibit that protein or reduce the synthesis of that protein is a smart approach to reverse the pathological process. And that is precisely what ARO-ANG3 does. It's an investigational synthetic, double-stranded hepatocyte-targeted RNA interference that specific silence ANGPTL3 messenger RNA expression in the liver. So next slide. We conduct a Phase I study that is shown here. And as we normally try to do and be very effective and fast, this study enroll normal healthy volunteer for a single dose, a multiple dose, and then we enroll a number of subset of population of interest to really evaluate the effect of ANGPTL3 in these different populations. The first one is patient with an LDL greater than 70 milligrams per deciliter on stable statin treatment. The second group is patient with heterozygous familial hypercholesterolemia. And this population was defined by either having the genetically confirmed or a Dutch lipid clinical network score greater than 6. And finally, patient with hypertriglyceridemia defined as TG levels greater than 300 milligrams per deciliter. All these patient received 2 doses of [ I/O ] ANGPTL3 baseline, day 29, and then we observed these patients up to day 113. And after that point, we continued observation in a long-term extension. Primary objective was to evaluate safety, of course, PK and PD parameters that I will show in the next slide. Next. In the heterozygous and non-FH patient, we tested 3 dose level: 100, 200 and 300 milligrams. And the HTG population, we only tested 200 milligrams. I just wanted to highlight a couple of things in the baseline demographic. The triglycerides as expected, you see the high levels in those patient with hypertriglyceridemia. And those were the patient who have lower LDL cholesterol but higher non-HDL cholesterol. Next slide. Here, the result on the top of the slide, we show the heterozygous population, ANGPTL3 on the left-hand side. And as you can see, all 3 doses, 100, 200 and 300, achieved a very significant reduction in ANGPTL3, and essentially, every single patient achieved a very consistent reduction, somewhere between 80% and 90% approximately. And that translate into about 30% to 50% reduction in triglycerides. On the bottom of this slide, you see the ANGPTL3 data and TG in the patients with non-FH. These patients also achieved essentially the same effect at the 200-milligram dose, 90% reduction in ANGPTL3 and about 42% in triglyceride. Next slide. Here, we shall go back one. Here, we show the LDL cholesterol and non-HDL cholesterol, very consistent reduction of about 30% to 35% in both and very consistent again the result with the non-FH population with about 30% reduction in LDL and non-HDL. I think it's important to mention that, of course, in non-FH population, they all were on statins. And about 2/3 of the patient in the heterozygous population were also on statin background treatment. So this 30% reduction is on top of statin optimal treatment. And the other thing I want to mention is the last dose occurred at week 4. And this study and the data I'm showing now is up to week 16. So 3 months after the last dose. And as you can see, we're seeing a very consistent effect, so we're exploring how long this effect lasts. Next slide. With regard to safety, you can see here the frequent AEs typically of any study of this type have contusion, vascular access site bruising, so nothing really important here. 2 subjects reported in SAE. One was ketosis related to dapagliflozin and dehydration and the other patient had a syncope and had a fibula fracture. Two cases of ALT elevation, 1 was mild and get back to baseline soon after the elevation and another case of a peak of 230 on day 29 and again, that case or that patient had ALT back to baseline at the end of the study and this did coincide with an episode of gastroenteritis. No adverse effect or change in the labs with regard to platelet or renal function, no patient discontinued from the study. Next slide. So in summary, ARO-ANG3 is able to suppress ANGPTL3 in all 3 populations we study. And here, I include the patient with hypertriglyceridemia as well by 75% to 90%. Triglyceride reduced by 30% to 47%, 29% to 35% for LDL cholesterol and very similar decrease for non-HDL cholesterol. In the patient with high triglyceride level, similar reduction in ANGPTL3, 75% reduction in triglycerides. And remember, the baseline triglyceride level for this population was about 700 to 800. And this was the patient with lower LDL at baseline. LDL did not change, but non-HDL decreased by about 56%. As I said, these results were consistent up to 12 weeks, but the study continues to evaluate how long this effect lasts. And with this favorable safety and tolerability profile, we are going to progress to the next level of development. And I'll show you in the next slide the Phase II and the Phase III program. Phase II study, we will initiate an IND here in the United States in the first half of this coming year, and we will start the study globally again in the first half of the year. The population of patients will be such that will help illustrate what are the right population we want to include on the Phase III studies. So about 180 patients. We're going to test 3 different doses. And again, the population will be patient with TG greater than 150 with an LDL greater than 70 on statins. So when we are done with that and define the dose level and describe in more detail the safety profile, we're going to move on to a Phase III program with 2 clinical trials. 1 Phase III on mixed dyslipidemia in about 1,500 patients. This will be studied and primary endpoint will be lipids, triglycerides and LDL and non-HDL cholesterol. And in parallel, we will kick off a Phase III cardiovascular outcome trial. The number of patients is going to be very large. This is a place holder for 15,000, but we need to do the homework to understand exactly who the patient population will be that will likely benefit from this intervention and how many we will have to achieve clinical significance in cardiovascular outcome. With that, I want to turn it over to Chris Anzalone.

Okay, thanks very much, Javier. And of course, thank you to Dr. Goldberg. And thank you to Vince and Jim as well for putting this on. It's a good second day of our webinars. Okay. So look, I think it's clear that dyslipidemia is a major cardiovascular disease risk factor. Residual risk persists even after standard of care, and that includes even after PCSK9 inhibitors. So there is a real opportunity there. We think that ANGPTL3 is a validated target for mixed dyslipidemia. And the landscape that we would approach with this target, we think it's attractive. ARO-ANG3 is the only RNAi candidate currently in clinical development against that target as was the case that we talked about yesterday in ARO-APOC3. So that leaves antisense oligos and monoclonal antibodies as the primary competition, at least at this point. ARO-ANG3 is expected to have more favorable dosing schedule than either of those. We're expecting a subcu dosing every 3 or 6 months. Antisense oligos are expected to be to dose monthly subcu and monoclonal antibodies at least right now are looking like they would dose monthly IV. But I understand that there is some work done right now on evaluating weekly subcu dosing. In either event, it does not feel like that would be competitive with our anticipated dosing schedule. And then finally, of course, we don't expect -- as we mentioned yesterday, we don't expect to see the ASO-related safety issues such as thrombocytopenia in ARO-ANG3. Next slide. So where do we go from here? As Javier said, we will begin our clinical next steps in the first half of 2021. So it's just -- we're just on the doorstep. We plan to initiate a Phase IIb study in triglyceridemic patients who are not meeting LDL goal, and this will set us up to eventually do a cardiovascular outcome trial once that's complete. We see at the other end of these studies a large commercial opportunity in mixed dyslipidemic patients. So what is unclear at this point is where ARO-ANG3 is going to be positioned vis-à-vis other treatment options. As Dr. Goldberg said, it is not clear if we will be up or downstream of PCSK9 inhibitors. But as far as I'm concerned, I think we have interesting opportunities either way. So if we are focused on secondary prevention downstream of PCSK9 inhibitors, we see a large market opportunity. Now if we can address primary prevention and the upstream of PCSK9 inhibitors, we see a very large market opportunity. We're -- obviously, we're okay either way, we think we have something to offer that's important. So whatever ARO-ANG3 ultimately is positioned, we think that many patients could have a powerful new set of options to decrease that cardiovascular risk. Of course, that -- we believe that is the case for ARO-ANG3. And as we discussed yesterday, we believe that that's the case for ARO-APOC3 as well, that we are moving towards a whole host of new tools that cardiologists will be able to use to further decrease cardiovascular risk in patients. So with that, I guess, next slide. I'll open the call up to Q&A.

All right. First of all, the panelists can turn your camera on, please? So our first question comes from Sonya Bhatia at Goldman Sachs. And sorry that we missed your question yesterday, I apologize for that.

No worries. This is Sonya on for Salveen. So quick question on -- we have 2 questions. The first is on the safety for heterozygous FH patients. There were 3 patients that had oropharyngeal pain and then also lightheadedness, loss of consciousness. Just wondering what the split was between the different doses and sort of how to think about it given there wasn't a placebo for this arm? And then another quick question as well.

Javier?

Yes. So the first comment was about the oropharyngeal pain? Didn't quite get the beginning...

Yes.

Yes. So this is a very frequent symptom you see in many different people, and there was 4 people in total that had that symptom, so we really didn't look at that any more careful. Because if you look at any study, these type of symptoms are very, very common, so that's one. And then with regard to the contusion, I believe, was the second comment. We talk to all investigators that were taking care of these folks, and there was no evidence that, for example, syncope will cause contusion or the fall, but all considered mechanical falls. So we don't really have any concern that there is something that could be related. And in fact, none of these events were considered by the investigator possible -- or probably related to the [ study growth ].

That's very helpful. And then the other question was on partnerships. You've previously mentioned that you might partner one of the cardiometabolic assets. Just wondering what your updated thoughts are for ANG3.

Yes. Thanks. I appreciate that. Look, during the year, we were open to partnering 1 of the 2 cardiometabolic assets, and then -- and holding on to ARO-AAT. As you know, we have -- we did a partnership on ARO-AAT with Takeda. We think that's a good partnership for the company. We think it's a good partnership to get that drug to patients rapidly. With that, we are planning at least right now to holding on to both ARO-APOC3 and ARO-ANG3. We think these are big opportunities. We think these are potentially important medicines, and we intend to commercialize them.

Sure. So our next question is from Shawn Egan at Citi, and he recently initiated coverage on us just this morning. So go ahead, Shawn.

Great. I appreciate the education. 2 quick questions for me. The Phase III noncardiovascular outcomes trial, does that have -- does that potentially support approval? And then my second question is, in this scenario that Dr. Goldberg laid out, where you have a mixed dyslipidemic patient that you treated with a statin and then you're kind of left with the scenario where do I treat them with PCSK9 or potentially this drug, I guess how important will it be better than -- it will be to be better than PCSK9 on outcomes? Or are there other ways to show that triglyceride lowering is important?

All right. Can I take the first one?

Yes.

So we haven't initiated any conversation with the FDA yet to propose that, that Phase III mixed dyslipidemia study of 1,500 patients with focus on biomarkers will be an approvable study, but that is the intention, and there is precedent for that, all the way from Zetia to Repatha. So we think that we have the case here, and we will initiate this conversation when we apply for the IND because in that document, we will propose the overall clinical development plan that will include both Phase III studies. So our intention is to have this conversation with the agency first half of the year. And yes, to propose that, that study should enable a filing and eventually approval?

So I can answer the other piece of it. So Shawn, you're specifically asking whether how to get the data to show that the triglyceride reduction on top of this marked LDL reduction will really be an added benefit. So it's going to take a huge trial. You may know that there's a couple of trials using fibric acids that are currently going on. You might also know there was a recent failure of second omega EPA/DHA kind of combination therapy after the -- that set the trial that looks so positive. I think people who do diabetes and cardiovascular disease have been impressed on the subgroup analysis of people with diabetes who have been on fibrates, including the ACCORD trial, where the triglyceride lowering component really looks like it makes a difference. But those triglyceride trials by themselves are cooking, and I think we're optimistic that it will show something extra.

And then our next question is from Alethia Young at Cantor Fitzgerald.

Can you hear me?

I can hear you now.

Okay. Cool. I guess I wanted to go back to your comments, Chris, about possibly post the PCSK9 market as a potential opportunity. Do you thing like if you went that way, that there might be a little bit more flexibility on maybe either a smaller study or maybe a lesser scale size because people would have been kind of refractory, and it kind of right-sizes the market a little bit more than just like the true opportunities that's in front of that?

Gosh, I'll hand it over to Javier to answer that. I don't know whether it's answerable. But Javier, do you have thoughts on that?

Will you restate it because I couldn't quite get the question?

So it seems like if you were going after PCSK9, that market is much smaller. So you might be able to run a smaller study or something more specific and not maybe evade the outcomes or maybe get to a point faster?

Yes. I mean we need to work on that a lot more. We need to understand the final profile of this drug across different patient populations. We need to understand what are specifically the patient population that have residual race in the context of what this drug is able to do. When we combine these 2 concepts is when we're going to have the right patient population, understand the event rate and eventually be able to power the study and size the study properly to be able to say cardiovascular outcome. But all that work is going on now, we'll continue. We will need help from Dr. Goldberg and others to really understand in the overall university of patient -- universal of patient at risk with cardiovascular event, who are the ones that will benefit the most from this intervention.

And just so far, and probably maybe this is for Dr. Goldberg, like how do we think about like a lot of interesting medicines like PCSK9, one of the great modern discoveries. But commercially, it's been very tough. Kind of what do you guys need that you're not getting. I mean the medicines are great. Is it just the price is too high? Or -- and I guess, is obviously in context of thinking about the Arrowhead opportunity going into another yet big market?

Yes. So as a clinician to get PCSK9 for patients is not so easy, that their insurance companies block and because of the expense of the medication. And so yes, that's going to be a big issue. I can't speak to manufacturing, maybe somebody else could do that, how you could price this compared to the cost of making and using monoclonal antibodies. But that's been the big -- one of the big problems in PCSK9, and that's why it hasn't been taken up as well as you might expect because it has such dramatic LDL reductions. What it doesn't do though is it doesn't lower triglycerides really very much. And so the people with diabetes still have some residual risk I suspect from those triglyceride particles. But somebody else should talk about the relative difficulties for pricing of making a silencing RNA versus antibodies, that's really what you're asking.

Yes, ultimately. I don't view us with ARO-ANG3 as competing directly with PCSK9 inhibitors. We do some of the same things that they do, but we also lower triglycerides, of course. And we think that's important. And ultimately, our hope is that what we can show is that with this medicine, we can substantially improve outcomes. And if we can -- look, if we can do that, then there's value there to be had. And at least the data so far would suggest to us that we are -- we should be optimistic that there is some real help there for patients.

Next question is from Pat Trucchio at H.C. Wainwright.

Just a question for the company. First, just regarding ANG3 and the payer landscape in mixed dyslipidemia, can you tell us what the expectations would be for payer coverage prior to completion of the CV outcomes trial? And what the expectations for the outcomes trial would be based on the data generated to date? And a possible time frame in which that data from the outcomes study could be generated?