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

Good morning, and welcome to the Arrowhead Pharmaceuticals Cardiometabolic Virtual Investor Event. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the Arrowhead website following the conclusion of the event. I'd now like to turn the call over to Vince Anzalone, Vice President of Finance and Investor Relations at Arrowhead Pharmaceuticals. Please go ahead, Vince.

Thanks so much, Tara. And thanks, everyone, for joining us today. We're here to talk about our cardiometabolic pipeline and some exciting new data we have. Go ahead in next slide, please. I'm Vince Anzalone, Head of Investor Relations for the company. Next slide, please. And just reminding everybody that we will be making forward-looking statements on today's call. So please refer to our SEC filings for risk factors. Next slide, please. Okay. So here is the general flow of today. I'll give some opening statements. Dr. Rosenson will talk about the data that we presented on the ARCHES-2 study of ARO-ANG3 and AHA a couple of days ago. And then Dr. Ballantyne will talk about the APOC3 SHASTA-2 study. Dr. Ballantyne will also describe the severe hypertriglyceridemia in FCS patient populations and the risk of pancreatitis. Dr. Rosenson will then talk generally about the lipid treatment landscape and the idea of residual risk of cardiometabolic disease. Our Chief Medical Officer, Javier San Martin, will then talk about journey of those 2 products from early development and the registration path in the patient populations that we're going to be focusing on. And then our CEO, Chris Anzalone, will give some closing remarks, and then we'll open up the call to some questions for the entire panel. Slide, please. Here's our panel today. I mentioned Dr. Robert Rosenson, who is from the Mount Sinai Icahn School of Medicine; and Dr. Christie Ballantyne from the Baylor College of Medicine. We're very lucky to have them join us today. They're both recognized experts in cardiometabolic disease. So thank you to both doctors. And then from the company, myself, Chris Anzalone, our CEO; and then Javier San Martin, our Chief Medical Officer on the panel. Slide, please. So before we go on, I just wanted to highlight an announcement that we made this morning that we're really excited about. So we have the olpasiran royalty stream from Amgen. We did a licensing deal with Amgen in 2016 for that product. It was formerly called ARO-LPA and then AMG 890. And we have sold rights to that royalty stream to Royalty Pharma for $250 million upfront, with also an additional $160 million in potential milestone payments downstream. Importantly, we retained ownership of all $400 million in potential remaining development, regulatory and sales milestones from Amgen. And so we have essentially an additional $560 million of potential cash coming from that product. So it gives us a couple of really important things. It brings a cash inflow so that we can invest in the rest of our pipeline or continue to invest in our pipeline as well as our platform. And then it also gives us some downstream economics should that product continue to be successful. Slide, please. And I wanted to highlight some of those data on olpasiran, and it really looks fantastic. I'm showing a slide here with the dose response and the curves for 3 different dose levels at 10 milligrams, 75 milligrams and 225 milligrams either at once every 12-week dosing or once every 24-week dosing. And I think this is a really good example of how far RNAi has come, but specifically what the TRiM system, our targeted RNAi molecule platform, what it can do. And this curve just looks exquisite. You can see early on, you get a high level of knockdown, essentially completely clamping new production of Lp(a) that stays down for a long period of time. And this is interesting pharmacology that we think is unique to RNAi and a good example of why we're so excited about our own liver programs and our partner programs. We think that each new product is progressively lower risk and continues to show consistent results. So we think this olpasiran data are potentially best-in-class. Slide, please. So here are the studies that we have ongoing for our own cardiometabolic pipeline. So the ARO-APOC3 program is called SUMMIT. There's 3 studies. One is called PALISADE. It's a Phase III study in the FCS population. That's active now in recruiting patients. SHASTA-2, which we reported on and we'll talk about today, is the severe hypertriglyceridemia study. That's fully enrolled and should have a full readout next year. The third study is called MUIR. That's in patients with mixed dyslipidemia. It's also a Phase IIb study that's fully enrolled. And Javier later will be disclosing new interim data from that study that we have not talked about publicly. And these -- all of these studies kind of help us to plan on what the Phase III look like. Again, Javier will talk about that as well. The ARO-ANG3 program is called Vista. There's 2 ongoing studies there. One is called Gateway in the HoFH patient population. That is fully enrolled as well. And then the ARCHES-2 study is in the mixed dyslipidemia patient population. And that's also data that we reported on an AHA that we will highlight again today. Next slide, please. So now I'll introduce Dr. Robert Rosenson, who will give an encore of his AHA presentation. Next slide, and Dr. Rosenson, please take over. Thanks.

Well, thank you for the opportunity to present the results of this Phase II trial. And ARO-ANG3 is an investigational sRNA inhibitor that we evaluated in patients with mixed dyslipidemia. Next. These are my disclosures. I'm involved in many clinical trials, Phase II, Phase III and original investigational work and the disclosures of my co-investigators. Next. So we're aware that dyslipidemia defined as elevated triglycerides, low HDL cholesterol levels are associated with increased risk of recurrent cardiovascular events even in individuals that are well treated for their LDL cholesterol level. And these studies have been demonstrated on the background of statin therapy, statin therapy plus PCSK9 inhibitors. The problem is that triglyceride-lowering therapies have failed to reduce cardiovascular events on the background of those therapies. And this raises questions, how to reduce residual risk by reducing cardiovascular events with a therapy that's different than that, that has been tested before, such as the PPAR-alpha agonist, the fibrates or the omega-3 fatty acids. There's been a lot of recent work with angiopoietin-like 3, and it's really a key regulator of lipid and lipoprotein metabolism with multiple modes of action that include inhibition of lipoprotein lipase and endothelial localized enzyme that is key for triglyceride, hydrolysis or catabolism; and then endothelial lipase, which has been less well studied. And there's a tremendous interest in the effects of endothelial lipase and disinhibiting that enzyme with this class of therapies. There have been studies that have shown that loss of function mutations in ANGPTL3 leads to more lipoprotein lipase activity, more endothelial lipase activity. And phenotypically, these patients have lower triglycerides, LDL cholesterol, VLDL cholesterol and HDL cholesterol. Despite the lower HDL cholesterol, 2 Mendelian randomization studies have reported lower rates of coronary artery disease. And importantly, patients who have biallelic or 2 mutations in ANGPTL3, those known as familial combined hyperlipidemia, have no adverse effects associated with that phenotype. ARO-ANG3 is an investigational hepatic-targeted RNA interference designed to specifically silence ANGPTL3 mRNA expression and mimic and ANGPTL3 deficiency. Next slide. ARCHES-2 is an ongoing double-blind, placebo-controlled parallel arm study in patients with mixed dyslipidemia. Who is the study population? Those individuals who are on stable diet and background lipid-lowering therapy, who have fasting triglyceride levels between 150 to 499 milligrams per deciliter, LDL cluster level is greater than or equal to 70 milligram per deciliter or non-HDL cholesterol levels greater than or equal to 100 milligram per deciliter. The endpoints of this study are listed on the right side of this slide: serum triglycerides; the ANGPTL3 levels; and other triglyceride-associated lipoprotein parameters, the non-HDL cholesterol, the apolipoprotein B and the remnant cholesterol. Importantly, for this class of medications, based on the failure of vupanorsen, the Ionis-Pfizer compound is to evaluate the safety of this class of medications with a highly-specific quantitative technique using MRI. So in this study, eligible participants were randomized into 3 groups: ARO-ANG3 50 milligram versus placebo, 3:1 randomization; ARO-ANG3 100 milligram versus placebo; or ARO-ANG3 200 milligram versus placebo. A total of 180 study participants. The interim analysis is shown when all subjects reached the 12-week cutoff point, and the dosing is every 12 weeks in this study. We do have data on MRI in a subgroup at week 24. Next. In this study, the baseline characteristics were well matched. It was predominantly middle-aged individuals, quarter women. Predominantly white individuals. They were obese. And in terms of the lipids, the triglyceride levels were greater than or equal to 200 milligram per deciliter or so. Even though the entry was 150, but the triglycerides, of course, the average is higher. LDL cholesterol of about 100, non-HDL cholesterol above 130. Elevated apolipoprotein B. Remnant cholesterol greater than or equal to 30 milligram per deciliter and the HDL cholesterol levels were low normal. Next. There was a dose-dependent reduction in ANGPTL3, ranging from 15% to 71%, and these values were obtained at week 8. More data will be forthcoming, but those were the data that were available at the time of this late-breaking clinical trial presentation. Triglycerides were reduced by 53% to 59%, so equivalent at the different doses. Next slide. But there was a dose-dependent reduction in LDL cholesterol ranging from 22% to 32%. That's going to be important when we distinguish ARO-ANG3 against the antisense oligonucleotide vupanorsen. There were also reductions in non-HDL cholesterol dose-dependent, 28% to 36%. Remnant cholesterol fell by 40% to 47%. Importantly is the mean apolipoprotein B fell by 13% to 21.8% at week 16. And the reason that this is important is because the failed triglyceride-lowering therapies such as the PPARs/fibrates in most studies with omega-3 fatty acids failed to reduce the concentration of the atherogenic lipoproteins as measured by apolipoprotein B. So this is an example we have triglyceride lowering, we have LDL cholesterol lowering, not an increase in LDL cholesterol seen with those other classes of medications. And most importantly, a reduction in the total number of atherogenic lipoproteins is shown by this data with apolipoprotein B. Next. As I mentioned, there were concerns with limited data with loss of function variants Mendelian randomization that there might be increase in transaminases, hepatic fat in those individuals. It was a very mild signal of -- review of that data didn't show any long-term adverse events in terms of cirrhosis or liver failure. But then the data with vupanorsen, the ASO from Isis and Pfizer raised questions about the safety of the pathway. So in this study, we evaluated hepatic fat fraction using MRI. And in the subgroup of 35 subjects with liver fat greater than 8% at baseline, additional MRI studies were performed. And what is very clear here is there's a dose-dependent decrease in hepatic fat up to about 30%. It's a different profile. Next. I'll just comment on one point that I've failed to mention in the last slide is that also unlike vupanorsen, where there was an increase in transaminases, there was only one person who had a tranche in increase in transaminase with no accompanied bilirubin. So it was not only safe on the liver, reduced hepatic fat, but there were no transaminase signals. So we look at the other therapies that have been evaluated that target ANGPTL3 in the trial with evinacumab in patients with severe hypertriglyceridemia and prior episode of pancreatitis, no change in hepatic enzymes and really no change in hepatic fat with a broad range of reductions up to 23%, but some patients had an increase in 39%. This paper will be forthcoming in Nature Medicine. What we didn't do but we need to do is look at the groups that were responded to evinacumab. There was no response in patients with familial chylomicronemia syndrome. We have 2 defects in a lipoprotein lipase or lipoprotein lipase pathway, but the therapy was effective in individuals with more severe hypertriglyceridemia, who had some preserved lipoprotein lipase activity. So looking at the efficacy and the liver enzymes or hepatic fat, and that population is something that we should do and that idea came forth after I presented these data. As I've mentioned several times, vupanorsen is an antisense oligonucleotide nucleotide directed against ANGPTL3 in patients with mixed hyperlipidemia are fairly comparable to what we studied in ARCHES-2. But unlike the safety on the liver, there was a dose-dependent increase in ALT and AST, more than 3x the upper limits of normal in 33% to 44% of the patients, but a dose-dependent increase in hepatic fat up to 76%. And based on that adverse lipid signal, I mean liver signal, the therapy is not going to be developed, and I think appropriately so. So to reiterate, what we showed with ARO-ANG3, similar population, no increases in transaminases, no increase in bilirubin and a dose-dependent decrease in hepatic fat up to 30% at the highest dose. These results are extremely encouraging regarding this pathway and the opportunities to treat some of our more difficult patients with mixed hyperlipidemia or refractory hypercholesterolemia, a topic that we can discuss in more detail later. Next. What about other adverse events? They were as expected in any clinical trial. Importantly, turn your attention to treatment emergent adverse events leading to drug discontinuation. This occurred in one individual. We had a myocardial infarction, a heart attack that the investigator felt was unrelated to the study medication and that was the one cause of death. But the safety profile was excellent and, again, as expected. Some people get infections, cold and things like that in any trial. So this was as anticipated. Next. So this interim analysis of ARCHES-2 suggest favorable changes in lipids, favorable changes in terms of safety. And to highlight, the ANGPTL3 levels fell by 71% at week 8. Again, more data will be forthcoming to later time points. Triglycerides fell up to 59%, again about what was seen with vupanorsen. And then -- but LDL cholesterol, unlike vupanorsen, fell not just by 8%, by 32% at week 16, which raises the question not only in terms of an ASO vupanorsen versus the sRNA ARO-ANG3 is having maybe a couple of effects on triglycerides, but differences in LDL cholesterol, which may support the fact that ARO-ANG3 is more effective in disinhibiting endothelial lipase in vupanorsen. I'm extremely excited and feel very comfortable about this reduction in hepatic fat. Many of these patients with nonalcoholic fatty liver disease are a challenge to treat because many of the therapies worsen the transaminases and sometimes they're sustained above threefold above the upper limit of normal, which requires a dose reduction or definitely more cautious approach. And then, of course, you're concerned about those individuals developing scarring or NASH, nonalcoholic steatosis. This reduction in hepatic fat -- this dose-dependent reduction in hepatic fat without an increase in liver function studies, I think, is really a game changer for these patients. Other adverse events were as anticipated. And only a single drug discontinuation due to an adverse event, which was a myocardial infarction. It's a high-risk population. So we can feel comfortable in concluding that these changes in serum lipids and lipoproteins, the reduction in ApoB, the reduction in remnant cholesterol really provide potential value for this treatment in mixed dyslipidemia as well as other patients who are difficult to treat even with a PCSK9 inhibitor. And again, the potential for reducing atherosclerotic cardiovascular disease events based on the profile is there and support for a Phase III trial is much needed. Okay. Thank you.

Dr. Rosenson, next slide, please. Now Dr. Ballantyne will give his encore presentation for the ARO-APOC3 program. Next slide. And go ahead, Dr. Ballantyne.

Thanks. Let's go to the next slide. So I'll be discussing on behalf of the investigators of SHASTA-2 study, ARO-APOC3. This was in patients with severely elevated triglycerides. Next slide. These are the disclosures from myself and coauthors. Next slide. All right. So why go after severe hypertriglyceridemia? Well, when you have very severe levels, you get a problem with -- an acute problem of pancreatitis. This is a potentially life-threatening disorder. And unfortunately, at the current time, we really don't have very good therapies for some of the individuals. So there's an unmet medical need. We know that APOC3 is actually interesting. It's carried on the triglyceride-rich particles. It inhibits lipoprotein lipase, but also acts in another mechanism that's independent of that, which is particularly important when we get towards some genetic disorders. The genetics have been very insightful, and it's really what led to the focus on APOC3. Individuals who have a loss of function variant, they have lower triglycerides, lower chylomicrons, lower postprandial lipemia. Really, the whole of the profile looks better. There's lower non-HDL ApoB, higher HDL. They have reduced coronary calcium. They have reduced cardiovascular events. And there's no known adverse effect in terms of being -- having these individuals who have a loss of function mutation. They are perfectly healthy. So this is the data and was following up to a promising Phase I study. Next slide. So it's a 3:1 randomization, 3 dosages; 10 milligrams, 25 milligrams and 50 milligrams. And it's really quite striking, the potency. You'll see the data coming up here. But these are low dosages of this agent. In terms of this, there was placebo controls for this, so I'd say, a 3:1 randomization. To get into the study of hypertriglyceridemia, greater than 500 milligram per deciliter up to 4,000, so you could be quite high to get in. And this was a study looking at the lipid endpoints along with APOC3. So triglycerides, non-HDL, LDL, HDL, the data that is being presented is an interim analysis. So this was the -- after 50% of subjects had reached to week 12 and received both dosages. That's 177 subjects had entered the study at the time of the data cutoff, which was 25th of July, and the data that's been shown is going up to week 16. Next slide. Patients were similar to the last study you just heard. A little bit younger, also obese. Not quite as high as the last one, but still BMIs are on 31. Predominantly white males. The triglyceride levels, the median now is around 700 in the upper quartile there. As you can see, IQR is around 1,000. LDLs tend to be lower in individuals who have very high triglycerides, and you can see these levels were relatively low. But the non-HDL cholesterol levels, cholesterol has carried in triglyceride with separate proteins is quite elevated. It's around 200. These individuals also tend to have very low levels of HDL cholesterol. So most of the cholesterol is what we would be -- what we call remnant particles. Remnant cholesterol is high. Next slide. So even at 10 milligrams, as you can see, 73% reduction. So 73% to 80% triglyceride reductions were also highly effective, 78% to 86%. Next slide. This was the same design as our last studies. The dose given at baseline and then at week 12. Non-HDL cholesterol reduced 34% to 45%. HDL cholesterol increased 76% to 99%. Next slide. So there was a slight increase. As I mentioned, these people have low levels of LDL. And when you lower triglycerides -- so when you have very high triglycerides, you're not catabolizing the particles. Those particles normally get converted to LDL particles and then get removed. So when you enhance life policies, you get some increase in LDL, but this was fairly modest here. If you look, you're talking about an increase. In terms of the absolute levels, for example, the median level at 25 milligrams went from 62.5 to 64.5. So these are small changes in terms of the absolute concentration of LDL cholesterol with large changes in regards to the reductions in non-HDL cholesterol, the view of the 25-milligram group. The non-HDL cholesterol in median dropped from 224 to 112, so 45% reduction. And we know is that in terms of the association with cardiovascular events, non-HDL cholesterol actually has the strongest association even more than LDL cholesterol. Next slide. As is seen in most of these trials have been done in the COVID era, the most common treatment emergent adverse event was actually COVID. I always look at in the studies of this size. They give you an idea really about tolerability, and you can get some safety signals. But one of the things I always look for is discontinuations. And as you can see here, that was quite promising. Treatment-emergent adverse events seen in drug discontinuation, there were 0 in this study. There was a slight increase in HbA1c. This was in individuals driven with baseline diabetes. There were 2 cases of pancreatitis. Those were both blinded, and so I don't know which groups they were in. Next slide. So in summary, this was an interim analysis, which showed a very nice efficacy in regards to reductions in the protein level of APOC3 up to 87%. Also, triglycerides reduced highly effectively, 86% reductions in non-HDL cholesterol and an increase in HDL cholesterol. It was well tolerated, and so this data was encouraging in regards to moving forward for a larger study, Phase III. Next slide. Okay. I'm going to give a little background in terms of what does this mean in terms of clinical care. And let's go to the next slide. So I'm Chief of Cardiology and Cardiovascular Research at Baylor College of Medicine. We have a center for cardiometabolic disease prevention. Next slide. So I was also a member of recent ACC guidelines in terms of what do we do about high triglycerides. So in this American guidelines, we're using -- we're measuring milligrams per deciliter, Europeans do millimoles. So we call in the United States, severe triglycerides is over 500. Triglycerides is 500 to 999, and you call it very severe is over 1,000. And we'll give some distinctions into why that is. Over 1,000 is much more of a potential. In terms of lipids, you don't have many emergencies. Very high triglycerides is one because you can get pancreatitis acutely. Now one comment in terms of -- remember, we measure triglycerides when people come in the clinic in the fasting state. That's usually after an 8- to 12-hour fast. Triglycerides when given a fatty meal may peak around 6 hours later -- 4 to 6 hours later. But individuals who have heart disease and diabetes, the peak is higher and it's later. So if your triglycerides are 200, reading studies where we give a high-fat meal, they go up to 600. And think about what happens in the regular day for an American. They eat breakfast. And what happens after 5 or 6 hours? They get the second fat when they get launch. And what happens in other 6 hours later, a third fat load, which is dinner. And if you want to really jack up the triglycerides, you do the experiment that happens in Houston all the time. And somebody goes out on Friday night and they go drink margaritas and have beer with chips and salsa and queso with enchiladas and refried beans. Now if you do that, you can really get your triglycerides up and so tend to go -- might have been 600, might end up being 1,200 after that. And at big weekend, they could end up into the emergency room with pancreatitis. So we are very concerned when we see these values because they fluctuate wildly depending upon what's happening with diet lifestyle. This one is diabetes with glucose. Next slide. Now desirable is less than 150. So the big part when we say elevated triglycerides is in the 150 to 500. So that's the brown part of this pyramid. When you go over 500, as much as smarter. And at the top of it are the individuals who have chylomicronemia. In the United States, we say that's over 1,000. Europe, they say 10 millimoles, which is 885. So these are the people who are at the highest risk for pancreatitis, and there is a monogenic familial chylomicronemia syndrome is the top of that pyramid with very, very severe elevations of genetic disorder in very challenging patients to treat. Next slide. So FCS is usually what we call this as a familial chylomicronemia syndrome. It's biallelic. We used to say, it's autosomal recessive, but you have 2 basically abnormalities that you inherit from your parents, and there's some canonical genes. These are all involved with microprotein lipase activity, which is LPL, APOC2, APOA5, LMF1 and GPIHBP1. What's much more common is what we call a multifactorial chylomicronemia syndrome. I don't like the terms here. Kind of implies that one is genetic and one is not. But these individuals actually a lot of them have heterozygous mutations. They have one effective copy, but they also have what we call a small variance, and we used to have polygenic risk scores for who is at a higher risk for triglycerides. So that is much more common than the FCS. And then we, as I mentioned, we have the people at 150 to 500, which is even more common. Next slide. Well, where does APOC3 play a role in here? It's very important as mentioned. If you look at these particles, so you make VLDL in your liver. It's a big particle of triglycerides. Gets converted to -- we have policies. You give those free fatty acids, which you use for energy. And this step of my process is very [indiscernible] activity of lipoprotein lipase. Other gene products are very important. ANGPTL3, GPIHBP1. So you have mutations and that you have big problems. Therefore, VLDL metabolism are also chylomicron metabolism. Next slide. So in regards to genetics. This is a paper that's in press. We've been working, and we're using it in the commercially available genetic testing, 3 academic [indiscernible]. And we looked at individuals, and there's this issue. Where do we -- what do we do with polygenic risk scores? And then also, there's a lot more people who have very high triglycerides. And this shows that if you have a single pathogenic variant, so you wouldn't meet the criteria of what we call right now familial chylomicronemia syndrome. If your polygenic risk score is high, you have a tremendous increase in both triglycerides and risk of pancreatitis. Now you've inherited one bad copy of a gene and then you have a high polygenic risk score, that is familial. So in ways our language that we're using to describe these is unfortunate because it implies that only one is genetic, but these individuals also have genetics. Why is this important? Well, it's important a little bit in regards to the orphan drug indication for FCS, which was obtained in Europe for APOC3 ASO, not in the U.S., but it's a very rare disorder. It's still a rare disorder in these individuals, but it's a larger population of people who have a single pathogenic variant along with a high polygenic risk score. Next slide. So I -- as a clinician, I hope that we move towards a little broader definition in that multifactorial chylomicronemia, which is substantially more common. It's maybe 0.1%. But as compared to 1 in a million, FCS estimate of between 1 in 250,000, 1 in a million. This is going to be maybe 1 in 500 or 1 in 1,000, I think, multifactorial with a genetic basis. Most of it has a genetic basis. Some of that could be poorly controlled diabetes along with other factors. But you have to have some genetic components to beginning to these levels of 1,000 or over. The biallelic familial chylomicronemia syndrome, very, very high risk for pancreatitis, frequently starting even in childhood in very difficult to treat, unresponsive to the available medications that we have right now. However, some of these MCS patients, the ones I talked about, who have a strong genetic basis, also are very challenging to treat and have increased risk for pancreatitis. And they probably had even higher risk for heart disease than the people with pure SES. Next slide. Okay. So the risk for pancreatitis goes up the higher your triglycerides. This is one showing this. Let's go to the next slide. And we where you really see it picking up very much is when you get over 1,000. So you can see that this is an odds ratio in here over 1,000, over 2,000, you see as a tenfold increase in risk over that. So that the higher your triglycerides, the greater the risk for having pancreatitis. Next slide. What about heart disease? Well, there's also a strong association as your triglycerides go up, we see an increase, particularly in atherosclerotic coronary disease, advanced myocardial infarction and ischemic heart disease. Some will also increase in stroke risk, too. So this has been shown in multiple studies. These people also tend to have problems with low-HDL cholesterol, obesity and metabolic syndrome. Next slide. And large genetic studies have clearly shown that if you look at individuals who have genetic variance with lower levels of APOC3, they have lower triglycerides over an approved lipid profile, and they have fewer cardiovascular events. Next slide. So it's an interesting molecule, APOC3 inhibits lipoprotein lipase, –independent pathways. But it also plays a role in lipoprotein lipase, independent pathway. Next slide. So this is something that's very important clinically because I mentioned this really severe disorder, they don't have any lipoprotein lipase activity. Next slide. So this is data from the Phase I. I'm showing this particularly with the focus on chylomicronemia, these people with very, very high triglycerides, over 880. Next slide. So in this study, there were a few patients who had genetically-confirmed biallelic FCS, 4 of them; non-FCS, they were 25. But out of that group, noticed 7 of them had a single pathogenic variant. So they had -- it doesn't mean they didn't have genetic component. These were very high triglycerides. As you can see, the FCS was 1,650; non-FCS at 1,381. Next slide. And this is very important. It worked in non-FCS. And we already knew this, there was an ASO vupanorsen that worked in non-FCS. The difference is you were giving 300 milligrams every week. It's 1,200 milligrams a month. And unfortunately, there were some adverse effects with platelets with that. So the drug was never approved in the United States. So here -- and this is really interesting in that inhibition of APOC3 works across the board. Even if you have genetically confirmed FCS, it still lowers triglycerides. Next slide. And the same was about the same that lowers APOC3 and that lowers triglycerides. The same in FCS or non-FCS. Next slide. Highly effective. So this was -- it was good to see what we had thought we would see in the questions with ANGPTL3 data that Bob has impressed is not so clear that ANGPTL3 will work in -- really doesn't seem to work in pure FCS. So it's a unique aspect of inhibition of APOC3. It even works in the most severe genetic cases, and it worked in this orphan drug indication of FCS. Also works throughout the spectrum in regard to patients with high triglycerides. So it's a promising treatment for patients who have unmet medical need. Next slide, I think that was it.

Thanks so much, Dr. Ballantyne. Dr. Rosenson will come back and talk about the cardiometabolic and lipid treatment landscape and the idea of residual risk of cardiovascular disease. Dr. Rosenson?

Thank you. Maybe we can turn to the next slide. So we're going to be talking about these triglycerides-rich lipoproteins. And you've heard some of the targets in the 2 presentations, and we'll delve into those in more detail. Next. ASCVD is -- remains the leading cause of mortality worldwide, and we've got therapies at lower LDL cholesterol, but we also can recognize that about 20% to 25% of those patients have increased triglycerides even with a controlled LDL cholesterol level. And this concept of residual lipoprotein risk contributing cardiovascular disease is one that has been discussed for decades. What component of the triglycerides contribute? Well, the triglycerides are carried in lipoproteins. And it's these triglyceride-rich lipoproteins and the cholesterol in those lipoproteins that contributes to the risk. One of those terminologies is known as remnant cholesterol. That has been evaluated in classical epidemiology as well as Mendelian randomization studies. In non-fasting remnant cholesterol, it is even more predictive of cardiovascular events than fasting remnant cholesterol. We also know that individuals with high triglycerides have an LDL particle that is less cholesterol-enriched, because through cholesterols for transfer protein, there's an exchange of the triglyceride for the cholesterol. And so LDL cholesterol underrepresents the risk. In apolipoprotein B or non-HDL cholesterol, it's more strongly related to risk in many populations such as those that are overweight, those with diabetes, those with HIV, those with chronic kidney disease. We're also aware, as Dr. Ballantyne mentioned, about apolipoprotein C3, plays a pivotal role in lipoprotein lipase activity, which is often down-regulated in individuals with the secondary disorders, multifactorial chylomicronemia syndrome with either one major trait or a polygenic triglyceride trait or individuals that don't have either one of those. And of course, the genetic causes of APOC3 deficiency are the more extreme and well-known conditions. So apolipoprotein C3 for individuals with more severe triglyceride phenotype is an important target, as Dr. Ballantyne mentioned. Next. These remnant particles do contribute to atherosclerosis. The remnant particles are taken up very avidly by the macrophages, which are the monocyte-derived cells that get into the vessel wall. And because they carry apolipoprotein B, they get in more avidly and there's more binding sites for their uptake into these macrophages and that contributes to the loading of those macrophages with cholesterol. And in addition, we know that these remnant particles, these triglyceride-rich lipoproteins can activate inflammation and they inhibit fibrinolysis or clot solution as well as increasing thrombosis. So there are many different pathways whereby TRLs increase atherothrombotic risk. Next. There are epidemiological studies that have shown increased risk of cardiovascular events with nonfasting triglycerides. I mentioned nonfasting remnant cholesterol. Other study show relationships with fasting triglycerides and fasting remnant cholesterol, but there's an opportunity to better characterize triglyceride-related risk in the postprandial state, and Dr. Ballantyne gave several examples, where that's a more typical pattern where we typically 3x a day snack. And those post-prandial responses are worsened by alcohol intake in the proceeding 72 hours and, of course, by the amount of fluid that you had the night before as well as your activity and your fat versus muscle mass. In terms of triglyceride lowering, those studies have, in large part, failed. But the REDUCE-IT study, which was icosapent ethyl, pure EPA compound, did show a reduction in major adverse cardiovascular events that was unexplained by the triglyceride lowering, whether it was the 18-milligram per deciliter reduction remnant cholesterol or what is considered to be more of grafts and anti-inflammatory effect of EPA is one open for discussion. And of course, you're probably aware that in that trial, there was a comparison with mineral oil, not a true placebo. And the mineral oil increased LDL cholesterol and CRP and may have amplified the differences between icosapent ethyl and a so-called placebo study. Enhanced proteomic analysis suggests that the inflammation with the mineral oil may have accounted for the differences in that trial, but a highly debated topic in cardiovascular disease prevention. Next. In terms of the trials of individuals with acute coronary syndrome or stable coronary disease, those individuals with high triglycerides are at a higher risk for recurrent events contributing to this concept of residual risk, but they also drive more benefit from statin therapy. And the statins that were used in these trials, atorvastatin, could be an effective triglyceride-lowering therapy, particularly used at high doses. In the bottom panel, we can see the triglycerides-rich lipoprotein cholesterol or the remnant cholesterol that increased -- was associated with an increased risk of cardiovascular events. So again, focusing on the triglyceride-rich remnants or the remnant cholesterol may be more proximate to the atherosclerotic process than just looking at the triglyceride carried in different lipoprotein fractions. Next. We discussed some of the genetic evidence that also confirms the classical epidemiology or observational data regarding remnant cholesterol, APOC3 and PTL3 is identifying people at increased risk for cardiovascular events. In this slide, we show the data that I alluded to in my earlier presentation about the loss of function variants in 2 of the Mendelian randomization studies that show lower triglycerides, HDL cholesterol, LDL cholesterol, cholesterol, but also lower rates of coronary artery disease and in the 2 studies, about 34% to 41%. So there have been a lot of debate with the reduction or the lower levels of HDL cholesterol and what this impact might be for coronary artery disease. But the endothelial lipase pathway for HDL cholesterol is not causally related to heart disease as shown in a paper years ago by Dr. Kathiresan when he was at the Massachusetts General Hospital. Next. In terms of APOC3, loss of function variant carriers, lower triglycerides and also lower risk of ischemic vascular disease events and this has been shown in 2 studies that appeared consecutively in the New England Journal of Medicine back in 2014. And so differentiating between the patient population, so it would be candidates for APOC3 versus ANGPTL3, is also one that we discussed at the AHA presentation. And as Dr. Ballantyne mentioned, I had the opportunity to lead up severe hypertriglyceridemia study with evinacumab. And that therapy, a monoclonal antibody drug against ANGPTL3, had no efficacy in individuals with FCS, a biallelic loss of function variants. But it did have a lot of benefit in lowering triglycerides, remnant cholesterol, non-HDL Class I patients with multifactorial chylomicronemia syndrome or unspecified hypertriglyceridemia. Next. So let's talk a little bit about angiopoietin-like 3. It's activity is activated by ANGPTL8. These are 2 proteins that are secreted by the liver and, therefore, are targets for RNA inhibition therapy. The ANGPTL3 inhibits lipoprotein lipase, the key enzyme involved in triglyceride hydrolysis and important not only for the clearance of chylomicrons, but also VLDL. What had later been discovered is the role of endothelial lipase, and we knew that loss of function variants yet had lower HDL cholesterol, but it didn't seem to have any impact on coronary artery disease risk. But more recently, endothelial lipase has been shown to be involved in the VLDL to LDL metabolism. What endothelial lipase does in the liver is it hydrolyzes the triglyceride in these very large VLDL particles converting them to a smaller VLDL particle that gets converted to a larger LDL particle that's more avidly cleared by the canonical LDL receptor. But in studies of homozygous familial hypercholesterolemia, we have biallelic mutations, loss of function budget variance in LDLR. No LDLR activity or less than 2%. You still get reductions in LDL cholesterol with the monoclonal antibody, evinacumab, and that indicates that the clearance of the LDL particle through ANGPTL3 inhibition is occurring independent of the LDL receptor. Next. So in an invited review for the Journal of American College of Cardiology, we were asked to write a review on triglycerides, and we came up with an algorithm that we assess the risk for whether they have cardiovascular disease or imaging evidence of coronary artery disease. We look at the family history, individuals with FCS. They'll pass on one of those traits to their children. We consider secondary causes such as obesity, poor diet, alcoholism, diabetes, hyperthyroidism, renal disease, liver disease, autoimmune conditions. We obtained conventionally a fasting lipid panel so we can calculate the LDL cholesterol, which again may not adequately represent the risk in patients with mixed dyslipidemia or severe hypertriglyceridemia, a risk that's more accurately captured by the non-HDL cholesterol, ApoB or LDL particle number. We can calculate or directly measure the remnant cholesterol. The study shows stronger relationships with nonfasting remnant cholesterol than fasting. We then might consider a genetic assessment of some of these major traits, but most individuals with severe hypertriglyceridemia or polygenic hypertriglyceridemia, not some of these rare disorders. And often, they've got single trait in many polygenes that push them into the triglyceride category in the thousands. We -- for individuals with the more severe hypertriglyceridemia, the chylomicrons we focus on strict low-fat diet for individuals who don't have the chylomicrons but the very low-density lipoproteins from the liver, we focus on reducing carbohydrates, of course, getting the weight down. Aerobic and resistance exercise is important to increase lipoprotein lipase activity. We look at other risk factors. We aggressively treat the LDL and think about triglyceride-lowering therapies. Again, much debate by icosapent ethyl because the study compared against mineral oil. There was another study that was presented at AHA that showed a reduction in events with icosapent ethyl on a secondary endpoint. The primary endpoint was not significantly reduced. I think the investigators were overenthusiastic about their projections of a 30% event rate, and they missed significance on that study, thus underpowered. Again, I talked about ARO-ANG. And Dr. Ballantyne talked about APOC3 inhibitor, which has roles in individuals with persistent elevation in triglycerides. Next. So to summarize, more and more evidence supports the role of triglyceride-rich lipoproteins, be it remnant cholesterol, APOC3, ANGPTL3 as contributors to atherosclerotic cardiovascular events. We discussed the loss of function variants in both ANGPTL3 and APOC3, lower triglyceride-rich lipoproteins and lower risk of ASCVD. We talked about the encouraging data from ongoing Phase II studies and the need to move forward to establish the efficacy in larger populations. And at least with regards to ANGPTL3 outcome studies for cardiovascular disease, APOC3 perhaps for preventing recurrent acute pancreatitis as well as the role for atherosclerotic cardiovascular disease in patients with a more severe triglyceride phenotype. Next slide.

Thanks so much, Dr. Rosenson. Next slide, please. Now Javier San Martin, our Chief Medical Officer, will talk about development of the 2 products and where we see them going. Javier?

Thank you, Vince. And thank you, Dr. Ballantyne and Dr. Rosenson, for such a clear and good presentations, and I will continue this by telling the journey for the development of these 2 molecules, ARO-APOC3 and ARO-ANG3. And in the clinic, this started in 2019. In the beginning, February and March, we kicked off the first in-human study for both molecules. That study -- the data from that study was presented actually at the American Heart Association in 2019. And here we are, 3 years later, present in the Phase II studies for the 3 indications that we can do these studies in the same meeting in the American Heart Association. And importantly, we will describe the strategy on how we see developing this drug moving forward. Next slide. So what to expect in 2023? We're going to do 3 Phase II study completions and dose selection, one Phase III study where FCS will be fully enrolled and we will have at least 3 end of Phase II regulatory interactions. A lot of work and very important achievement that we need to do in 2023. That was one of the key reasons why we did this interim analysis of our Phase II study to really get the information necessarily as possible that will serve us well to define the patient population, the indication that we want to pursue and how we will design these studies and eventually execute that. So they really define the registration path is what we're going to do next, and that's why this interim analysis was very important. Next. I'll start with ANGPTL3. As you know, a key regulator of lipid and lipoprotein metabolism, worked both by inhibit lipoprotein lipase and endothelial lipase. So inhibit ARO-ANG3 is the unique mechanism of action to address hypercholesterolemia in specific -- in addition and difference of other LDL cholesterol-lowering therapies. This drug may address unmet needs in patients with specific genetic mutations, for example, those with dysfunctional LDL receptors such as HoFH and HeFH population. And also may be added to other LDL-cholesterol lowering therapy in addition to achieve goal as is described. Next slide. So these are the 2 populations that we want to address with ARO-ANGPTL3. The patient with heterozygous familial hypercholesterolemia. These patients appeared to have an LDL higher than 190 milligrams per deciliter, and that can lead to the increase in ASCVD. About 1.4 million patients in the U.S. have this condition. Then there is a very specific and real condition called homozygous familial hypercholesterolemia in approximately 1,200 patients in the U.S. These patients tend to have very, very high LDL cholesterol, more than 400 and, of course, have a very increased risk of cardiovascular disease early in life. Next slide. Here is the data that was already presented earlier today by Dr. Rosenson. On the right-hand side of this table, you see what he presented in the study of mixed dyslipidemia with the 3 doses of range, 50, 100 and 200 milligrams. So the LDL on the first row shows a 20% to 30% reduction. And I want to show you that from the study 101 in the next column to the left, we have the patients who had HeFH-defined genetic -- those patients have evasion, LDL cholesterol of about 130, and they also show a decrease in LDL of approximately 24% and also decrease in non-HDL of 26% and ApoB of 14%. And also, the patients with the 101 study in normal healthy volunteers who actually have a relatively high LDL at baseline, 131. They have about 40% reduction in LDL. So what I wanted to highlight is across different populations with high LDL with or without starting background therapy, we see a consistent decrease in LDL, non-HDL and, importantly, ApoB in the range of 15% to 30%. Of course, triglycerides was decreased across the board in all these populations and regardless of the dose selected. Next slide. So ARO-ANG3 in summary has the ability to reduce LDL cholesterol between 20% and 40%. Non-HDL 30% to 45%. ApoB 15% to 30%. Triglycerides, 40% to 65%. And importantly, as Dr. Rosenson highlighted, decrease liver fat by about 30%, which is a very key and important safety feature. So these favorable effects across various lipid parameters may translate into positive change for patients with familial hypercholesterolemia syndrome. This also will be likely to Q3M subcutaneously, and that could enhance long-term adherence compliance and effectiveness. Here is the plan moving forward. Data readout for this program. The study ARO-ANG3-2001 of mixed dyslipidemia will be read at the end of this year. That will enable an end of Phase II meeting at the first half of 2023 and soon thereafter initiate the Phase III program. This program, we also have the study HoFH-2003. That is fully enrolled. This is an open label study in 16 patients, and this study will read out in the first half of 2023. At that point, will lead to an end of Phase II meeting with the intention to develop this drug for that indication as well. Next slide. Now we'll switch over to ARO-APOC3. So we speak about these 2 different syndromes. Those patients who have high risk of pancreatitis due to severe hypertriglyceridemia syndrome and patients where they still have residual risks in the atherosclerotic cardiovascular disease group with mixed dyslipidemia. Next slide. So as has been said today, the APOC3 is the key regulator of lipid and lipoprotein metabolism by both lipoprotein lipase creates an independent pathway. ARO-APOC3 improves multiple lipid parameters and may provide clinical benefit in a broad group of patients with dyslipidemia. Now we'll divide them in 2 major groups. The number one is patient to reduce the triglycerides in patients with severe hypertriglyceridemia, including FCS with intention to reduce the risk of acute pancreatitis. And second is reduction in residual cardiovascular risk factor by decreasing APOC3, LDL, ApoB, remnant cholesterol in patients at risk for cardiovascular disease. I will first start with the first population of patients with significant hypertriglyceridemia. Next slide. So here, you can see on the figure that the population of severe hypertriglyceridemia contains 2 groups; those with familial chylomicronemia syndrome, which is a very well-defined genetic disease. Again, patients have extremely high risk of pancreatitis with impact in quality of life. This is an ultra-rare disease with approximately 500 patients in the U.S. And patients with severe hypertriglyceridemia, which is a much more frequent condition with about 4 million people do exist in the U.S. that also have increased risk of pancreatitis. And again, the goal of therapy in these 2 population is decreased triglycerides, below that threshold where pancreatitis will be decreased significantly. Next slide. Yes. Again, I wanted to review the data that was presented earlier today as well. This is to the left, the Phase II study on severe hypertriglyceridemia that's 1 in 10% today. The baseline TG levels was about 700. And as you can see consistently across all 3 doses, we see a 77% to 85% reduction. Importantly, in the other 2 populations of patients with multifactorial chylomicronemia in the Phase I study of FCS with baseline TG levels of about 1,700, the relation was exactly the same, about 85% to 87% from baseline. And that means that the majority of patients decreased below that threshold where pancreatitis has decreased. Also in this population, we see a significant decrease in non-HDL cholesterol and an increase in HDL cholesterol. So despite the goal of therapy here is the significant decrease in triglyceridemia with intention to decrease pancreatitis risk, we see other potential benefit effect in the other lipids. Next slide. So what's the plan with this program? So we have a Phase II study in severe hypertriglyceridemia ongoing, fully enrolled. And the readout will be in the second half of 2023. That will enable an end of Phase II in the first half of 2024, and we expect to initiate the clinical program for severe hypertriglyceridemia prided after. Biallelic was developed in the growth for FCS. The Phase III study is ongoing. About 50% of patients are already enrolled. We expect to complete enrollment in the first half of next year. One year later, the study will be completed and readout and that will trigger our first new drug application here in the United States. Next slide. So now let me switch over to the other indication in which we want to address the residual risk in cardiovascular disease, and I will first present new data from the interim analysis of the ongoing new study in mixed dyslipidemia. Here, the study design of our Phase II study on APOC3 in patients with mixed dyslipidemia. We enrolled patients similar to the study on ANG with TG estimation between 150 and 500, LDL collateral greater than 70 or 100 milligrams of deciliter on stable statin therapy. Especially, we're randomizing 4 cohorts at 3 different doses, 10 milligrams based on week 12; 25 milligrams; and 50 milligrams. And also for cohort, where we enrolled patients on 50 milligram dose at baseline on week 24. Those cohorts was randomized 3:1 to active treatment to placebo. The endpoints are on the left-hand side of this slide. The classic lipids, triglycerides, ApoC, non-HDL, ApoB, LDL and so forth. So this data is also an interim analysis that we love the database when more than 50% of patients reach the week 12 visit. Next. Here are the baseline characteristics of this study. About 60 years old in average, halves were female. Most patients were white. BMI in the service as expected for this population. Triglycerides about 220, well distributed across the different treatment groups. LDL cholesterol about 110. And again, these patients were in baseline statin therapy. And non-HDL, 150 and, again, well distributed across the different treatment groups. Next. Here, the results ARO-APOC3 reduction was in the range of 70% to 88% at the doses of 10, 25 and 50 milligrams at week 16. Triglycerides reduced as a consequence between 60% and 73%, and very consistent across the 3 doses on the patient population. And remnant cholesterol, importantly, decreased between 45% and 60%. Next slide. LDL as per Hopkins calculation decreased between 15% to 23% in this population on top statin therapy. Non-HDL decreased by 24% to 30%. And importantly, also HDL increased by about 50% to 70%. Next slide. Here's the summary of safety. In this study in order to know the decline, we present TEAEs as a combined all groups. Again, very typical is that you see in a clinical trial like this and in the time of COVID, headaches, arthritis, different respiratory and urinary tract infections, so nothing unusual. There was a change in A1c at week 16, but higher in the treatment group, 0.17% to 0.36% with no changes in the procedure. Next slide. So now let me go back to the topic that Dr. Rosenson discussed earlier today, which is a concept of residual risk in cardiovascular disease. And here, there are 3 data points that he mentioned. One is the Copenhagen general study and Mendelian randomization study, where it clearly shows that remnant cholesterol -- higher level of remnant cholesterol associated with higher incidents of ischemic disease, including myocardial infarction, stroke and mortality. The next panel shows from the TIMI-22 that people with low triglycerides levels have low risk of cardiovascular disease in statin-treated patients. And finally, APOC3 in itself, patients who have higher levels of APOC3 seems to have higher rates of cardiovascular disease. So next slide. So again, here are the typical atherogenic lipids that we will try to address with this intervention: LDL cholesterol, VLDL, remnant cholesterol, elevated triglycerides and low HDL. The estimation is the approximately 12 million people in the U.S. will fulfill that criteria of mixed dyslipidemia and excess residual risk for cardiovascular disease. Next. Again, here, I wanted to show how, again, improvement in the different parameters that matter for this population. The right-hand side is the study, mixed dyslipidemia study. That is just the same, where we show a 20% to 25% reduction in LDL cholesterol. The same we have observed in the Phase I study in the patients that were considered healthy volunteers. But at baseline, they have a relatively high LDL cholesterol in the range of 150. Non-HDL cholesterol also decreased in all these different populations and treatment groups. And importantly, ApoB decreased by 25% in average across the different studies. Here, as expected that we showed before, a significant decrease of about 60% and HDL increase. So this completes the panel and the profile of this effect in this particular population. Next slide. Okay. Now I wanted to show you how a patient looks like with mixed dyslipidemia, and this is from the Phase II study. And we take the average of the baseline to describe how a mixed dyslipidemia patient's lipid profile looks like. At baseline, pretreatment APOC3 15, triglycerides about 220 milligrams. Those patients post-treatment decreased to 77% to 65% of reduction from baseline. In non-HDL cholesterol, the baseline was 150, rather high, 28% reduction. But now represent 108 milligram per deciliter. LDL went from 110 to 88. ApoB 95 to 76 milligrams per deciliter. Remnant cholesterol, importantly, decreased by 60% from 46 to 18, and HDL cholesterol increased 50% from 42 to 63. So each of these 2 different patient profiles, the pretreatment patients and followed them for 5 to 7 years and think about the risk of developed atherosclerotic disease and cardiovascular events due to mixed dyslipidemia because every single of this parameter are the ones related to the residual risk that increase the risk of cardiovascular disease. The patient received ARO-APOC3. And you can see the profile that, that person will have over the same period of time and how that may affect and hopefully prevent cardiovascular disease moving. So that's where we are and where we're going with ARO-APOC3 in mixed dyslipidemia. Phase II study is fully enrolled. We will read out that study in the second half of 2023. Soon thereafter, we're going to have an interaction with the regulatory agents and have the end of Phase II meeting where we will discuss and hopefully agree on how Phase III cardiovascular trial will look like. Next slide. So why we did this in general and why it's so important? Because we need to start to work now to identify who are the right patient population, what we calibrate with this drug. Patients with a clear risk despite LDL cholesterol control, patients with already established cardiovascular disease, patients not meeting LDL cholesterol treatment goal. And in order to really define who are the patient population, a lot of work needs to be done modeling to estimate event rates and the effect size, understand the length of the study, the dose and the dose interval. And this interim analysis really help us to start to plan and work ahead of time to be ready for the end of Phase II meeting that will define this important Phase III study. Next. So we get to this point in 2022, we clearly define our cardiometabolic strategy. We're pursuing 5 indications. So we aim to address 5 different diseases, 3 with ARO-APOC3, familial chylomicronemia syndrome, severe hypertriglyceridemia and treatment of mixed dyslipidemia with intention to decrease cardiovascular event. ARO-ANG3 will be focused on homozygous familial hypercholesterolemia and heterozygous familial hypercholesterolemia. All these 5 indications have a clear regulatory path. We are about to start the late-stage development. Now, I will pass this on to our CEO, Chris Anzalone. Chris?

Thanks very much, Javier. And thank you to all the speakers. Dr. Rosenson and Dr. Ballantyne, Javier, of course, and Vince, and thank you all for joining us today. Next slide. We believe that RNAi is on the cusp of changing the way that we treat cardiometabolic diseases. Leqvio could change the way the PCSK9 market looks. Olpasiran could change the way that we address Lp(a). ARO-ANG3 could change the way familial hypercholesterolemia is treated. ARO-APOC3 could change the way triglyceridemia, and dyslipidemia can be treated. Not so long ago, the only treatments for these have been changes in diet and statins. So these innovations, we think, represent substantial leaps forward, an era that has developed 3 of these 4 drug candidates. Next slide. Our business model has relied on leverage. Our idea was to develop broad RNAi capabilities and then apply that to multiple tissue types in order to create a variety of drugs to treat a variety of diseases. This model, this strategy was designed to maximize our return on investment as well as to maximize the clinical reach of our technology. Next slide. We believe that the cardiometabolic franchise we have is an example of this leverage. We have 2 drug candidates addressing at least 5 diseases potential to treat millions of people. Currently, we are running one cardiometabolic Phase II, and we expect to begin 4 additional over the next 18 months. Next slide. We intend to commercialize these drug candidates in a staged approach from small market to large markets. For ARO-ANG3, that means beginning with HoFH, conducting a larger HeFH studies and eventually expanding the label and entering that market. For ARO-APOC3, that means starting with FCS. Doing longer studies against severe hypertriglyceridemia and expanding the label into that market and eventually expanding to the very broad dyslipidemia market. We believe that this approach enables us to interact with patients early, allows us to learn from the market before addressing larger indications and allows for a build-out of a commercial infrastructure at a measured pace. Next slide. These are expensive endeavors to be sure, and we believe we have access to sufficient capital to pursue them. As of our last 10-Q filing, we reported $582 million of cash. We currently have 6 partnered programs with 5 different companies, and we expect to receive milestone payments from each of those companies over the next 12 months. The breadth of our platforms, we expect to do around one new partnership every year. And as we disclosed earlier today, we sold the rights for royalties from Amgen on future sales for olpasiran for $250 million upfront. We are also eligible to receive additional $160 million from Royalty Pharma during the development of the drug candidate, and we are also eligible to receive up to $400 million in milestone payments from Amgen. Next slide. We believe that we are entering a golden age of treating cardiometabolic diseases. Multiple tools are being developed to treat multiple risk factors, enabling physicians to dial in personalized treatment paradigms and hopefully providing millions of patients with new hope, and we believe that Arrowhead is leading the way. With that, I'd like to open the forum up to questions.

[Operator Instructions] So our first question is from Maury Raycroft from Jefferies.

Maybe starting off for the company with next steps for development. How do you think about pricing for APOC3 and FCS with consideration of moving into a higher volume sHTG in mixed lipidemia settings? And for the sHTG in mixed lipidemia settings, based on the effect size from your Phase II data, do you have a good framework for what Phase IIIs could look like?

So I can address the pricing question by now addressing it. We have been thinking about this, of course. We've not disclosed what we are thinking. I will say, though, more broadly, we do think that as we broaden the label out, we can decrease the price. As we expand the markets, we can decrease prices. So in other words, for APOC3, assuming that we are approved in FCS, that will be priced as an orphan drug. It's a very small market and it would be unclear at that point whether or not we're going to see approval for large markets. Once we do get approved for sHTG, we believe we can lower the price. And then again, we can lower the price once again and once we are approved for dyslipidemia for larger markets. Javier, do you want to address the Phase III?

Yes. So the phase -- we're very confident to run both the HoFH Phase III and HeFH Phase III studies. The data for mixed dyslipidemia population looks very similar to the antibody to ANGPTL3. So I think we're very confident that we're going to have similar days probably in HoFH. These are patients at high risk, whether that met medical needs remains there. And an extra 20% to 30% decrease in LDL and 20% decrease in ApoB is likely to be beneficial and hopefully, it translates into prevention of cardiovascular disease. So we believe that not just that, but also the convenience of every 3 months subcutaneous injection versus every other week subcutaneous injection is likely to be a beneficial feature for patients and the system in general.

Got it. And maybe one follow-up question for the doctors. For the APOC3, more ANG3 knockdown and triglyceride reduction levels, it seems consistent for both programs. But do you have ideas on why the HDL-C and the non-HDL-C changes are more variable? Do you have insight into certain patient populations where results are more predictable?

It's a different mechanism of action. And so APOC3 does not inhibit endothelial-like base. I mean it's not involved with that. The -- one of the things that happens with APOC3 that was shown in the early days with the [indiscernible] that there's a tremendous reduction in postprandial lipemia. So when you eat a fatty meal, you normally have all these triglycerides and proteins start getting around for hours. That gets tremendously -- they get cleared out very rapidly. And mechanistically, if you have less postprandial lipemia, you have higher levels of HDL cholesterol. So at least in my mind, and this was going back to some work [indiscernible] from the past where they did in the '80s that they were feeding the HDL cholesterol is like the hemoglobin A1c for diabetes. It's the way you can assess for many people postpone lipemia, which also fits with the thought that it's HDL cholesterol is a marker of risk, but we've not been able to change the risk by changing HDL. However, I think if you were to really reduce postprandial lipemia, that is doing something that's highly beneficial in terms of reducing atherosclerosis. So it's a different mechanism of action in terms of what it's doing it now. In HDL, to me, it's so intriguing in terms of the paper that came out that Bob, how effective it is for homozygous FH. We always thought everything was the LDL receptor and traditional pathways, and it's always tough to find that 50% reduction. But it was clearly from the genetic studies, they have lower levels of HDL and they have less atherosclerosis. Bob, do you have a comment?

Yes. So the endothelial lipase mediates the cluster loading of the HDL particle. The biological activity of HDL is in part related to macrophage cholesterol efflux, but most of the attention by people in the field are focusing on the HDL proteins or the HDL proteome. And HDL's got anti-inflammatory, antioxidant, anti-infective properties. But I'm not concerned about the HDL cholesterol because of the specific pathway that years ago had already been vetted in terms of Mendelian randomization studies. The fact that you get a reduction in HDL cholesterol says nothing about the function in terms of its HDL proteome. As Dr. Ballantyne just mentioned, the ANGPTL3 is quite novel as a pathway. Not for its triglyceride-lowering effect, which is easy to predict from the lipoprotein lipase, but it's really the effects on disinhibiting endothelial lipase and how that is involved in not only intrahepatic VLDL remodeling, but more importantly, the clearance of the LDL particle from the circulation that's working independently of the LDL receptor. We have patients with heterozygous familial hypercholesterolemia. Maybe as common in 1 in 70 in French, Quebec and Lebanon to 1 in 244 to 1 in 311 throughout the world. It's a common disorder where you have one LDL receptor that doesn't work, and not everybody responds to therapies that up-regulate the elder receptors such as statins and PCSK9. So there's a huge unmet need for that condition, which, of course, was present before that individual was born. And the cumulative burden of the cholesterol over one's lifetime has identified those patients for high risk and the types of patients that Dr. Ballantyne see quite regularly. And that's, I think, where ANGPTL3 has got a very unique profile for not only HoFH, but also the refractory HeFH population.

Our next question comes from Joel Beatty from Baird.

For the APOC3 agent, what's the impact of the LDL increase when considering how to power the OUTCOMES trial?

Yes. So I want to clarify that the LDL increase was seen only in the patient with severe hypertriglyceridemia. In patient with mixed dyslipidemia, we don't see an increase in LDL. Actually, we do see a decrease in LDL in non-HDL and ApoB. But it's an important question. That's why I said it's very important, this interim analysis, because we need to model all the risk factors that this stroke addresses and how that might translate into reduced risk of cardiovascular events. So that's why we did this interim analysis. That's why we're embarking now in doing a lot of work to really understand how to design and power the study. But I will reiterate that in patients that we're targeting for the cardiovascular indications, the extension LDL is a 20% decrease as well as it in ApoB and non-HDL. So the data is very consistent and solid in that population.

And just point out, this is very different than which you saw the -- with the trial with Pemafibrate, the PROMINENT study. Not surprising at all that it failed because we already knew from a prior publication, we saw this years ago that when you have high intensity statin plus its fibrate, you don't get any further reduction in non-HDL cholesterol or ApoB. And what we've shown actually in both studies, there was very significant reductions in non-HDL cholesterol in the mixed dyslipidemia and ApoB, so these are quite different than the fibrate studies.

And also for APOC3, what were the serious treatment emergent adverse events that were in 6% of patients?

Say that again.

What were the serious treatment emergent adverse events?

I can get this later. I don't have it quite right now, but we're going to look for, and I'll give it to you later.

[Operator Instructions] So our next question comes from Madhu Kumar from Goldman Sachs.

I guess kind of the first one, how should we think about the trial design for a -- for the severe hypertriglyceridemia trial in terms of pancreatitis events? Like what do you think are kind of the parameters there? And I guess kind of related to that, is there a notion to stratify on over 1,000 mgs per deciliter of triglycerides versus just over 500?

Yes. That's a great point. So we're really assuming, of course, a year ago, the Phase II study and the Phase III study in severe hypertriglyceridemia to the FDA and many other regulatory agencies, and the conversation with the FDA about how the Phase III study will look like already started to happen. And there is a clear path forward in which there is no need to demonstrate reduction in pancreatitis, reduction in triglycerides to the level that is likely to translate into a reduction in pancreatitis. It's what is going to be necessary and we know that we can do that. So we don't need a pancreatic for the approval. However, we want to enrich the patient population in the Phase III studies to really try to have a chance to see reduction in pancreatitis as the study will be designed looking at the subgroup analysis, pulling the data with the FCS population. So we think it's important. We think it's important for reimbursement and payers to not just demonstrate the improvement in the surrogates. Even though in this case, a surrogate really translated into a clinical benefit. But we aim to collect the information, have an adjudication process, and as I said, and reach the population to have as many cases of pancreatitis as possible to be able to show the clinical benefit within the Phase III study. The specific design of the Phase III studies are not quite defined at the moment. But your point about certification by level of TG makes a lot of sense, and it's likely to be one of the specification factors. Whether we do a large study or we do 2 smaller studies is something that we're discussing. Whether one study would be placebo-controlled or other might be active control is another consideration because that can help to really display the value of ARO-APOC3 in severe hypertriglyceridemia. So again, that's why it was so important to do this interim analysis, and they were to design those studies. This has started now.

Okay. So maybe tossing this question to the panel, a follow-up to that is, how long do you think you have to see triglyceride suppression? Do you start seeing that translate into a reduction in pancreatitis rate?

Direct to the panel. Dr. Ballantyne?

The benefit in terms of reduction in risk for pancreatitis occurs immediately. That's a different thing in terms of the accrual rate of the events of pancreatitis. You follow me? So patients get immediate benefit by treating them. It's just that the issue is the rate of any individual -- just because you will have triglycerides doesn't mean they're going to have pancreatitis immediately. So you end up looking at -- and this is going to look at in certain trials. It depends what are the baseline characteristics of the population you enroll in the study. The higher the triglycerides, then you're basically -- and also if they've had a prior episode of pancreatitis, the greater the likelihood of having pancreatitis. Those trials are quite difficult to do pancreatitis trials as your primary endpoint. They tend to have the larger sample size and order duration as compared to looking at a surrogate of triglycerides. But the FDA has been pretty clear. I think it was mentioned that they've allowed an indication for treatment of surrogate of triglycerides based upon triglycerides reductions.

I agree with Christie because we are involved in that severe hypertriglyceridemia, acute pancreatitis study. And the reduction of triglycerides with monoclonal ANGPTL3 in patients without FCS was about 88%. And there were a few episodes of pancreatitis. But the dose used in that trial, 15-milligram per kilogram IV every 4 weeks, was not sustained over the 4-week period of time. And then you saw this increase in triglycerides and more pancreatitis. I think the more fundamental issue, and I agree with Christie, that it's very difficult to do a prevention of acute pancreatitis study. And we just -- the sponsor for that trial, Regeneron, pulled to plug on that trial because of the difficulty to recruit. But keep in mind that once somebody's had an episode of pancreatitis in the preceding year, likely they're going to have another episode has increased about twenty-threefold. And if they've had 2 or more episodes in the preceding year, it's increased about forty-fivefold. And these people suffer immensely really affecting their social relationships or quality of life. And it's a tremendous high unmet need. So when Javier mentioned the issue about enriching with people that had prior pancreatitis, acute pancreatitis, I think that's the way to do it in order to enroll sufficient numbers of individuals. And of course, as both Dr. Ballantyne and Javier mentioned about severe hypertriglyceridemia being accepted surrogate for approval by the FDA for the prevention of acute pancreatitis is spot on.

Our next question comes from Luca Issi from RBC Capital.

You guys hear me okay?

Yes.

Terrific. Congrats on all the progress here. I have just 2 quick one. Maybe the first one for Chris. Can you just expand a little bit more on the strategic rationale behind this deal for LPLA and why you think it was struck unfavorable economics? Some debate out there. So we'd love to hear your thoughts there. And then maybe for the panel for both APO and ANG. I think we've seen a numerical increase in HbA1c for both molecule versus placebo. Wondering if you can comment on the significance of that and maybe implications for patients that are already diabetic at baseline.

Sure. I'll address the olpasiran monetization first. Look, that's a good deal for us. It's a lot of money upfront. We still have access to the $400 million of milestone payments from Amgen as well as $160 million of milestone payments from Royalty Pharma. So we still see more upside as that drug is developed and get to market. Look, we think it's a good drug, but it makes sense to us to monetize it now because, as you know, we have a very large pipeline, and I think we can create an awful lot of value in the near to midterm with that sort of capital. So it just made sense to accelerate, if you will, of the monetization of that.

Dr. Ballantyne or Dr. Rosenson?

Javier is probably the right person to answer about the -- in terms of the question of safety, but this is where I would say. This is where you need -- in general, this is a Phase II/III different dosages. You need really -- this is when you like to see the completed study, have all the information for it so you can truly evaluate A1c levels fluctuate, and then you need to see what it looks like over time. But Javier, why don't you provide...

Yes, yes. So well, we see these small changes in A1c in these studies was mainly driven by a small subset of patients who have poorly controlled diabetes at baseline. So we didn't see any trend in the patients who did not have diabetes. There was no cases of nuanced diabetes. And again, this was in a really small group of patients. It was mainly in the highest dose, so we really didn't see any major significant difference in the 2 lower dose for both programs. So we think that this is not impacting all our design for clinical trials. Of course, in cardiovascular clinical trials, you had to enroll patients with well-controlled diabetes. That was in the case in this Phase II study, but that's obviously the norm for any cardiovascular study -- Phase III study. So this really has been seen with other lipid agents. And again, it doesn't change the strategy. It doesn't change the design of the study with the exception that, of course, we will clearly define what is well-controlled diabetes for patients who will come into this study.

I just want to make a comment. In the ANGPTL3 program, there was quite a striking imbalance in terms of baseline anti-diabetic therapy. And the placebo group had more individuals on GLP-1 agonist, which the onset of action through the weight loss and also the improvement in glycemia usually occurs later on. And then the other groups had more insulin which, if they're not making adjustments in the background therapy, those individuals tend to gain weight and then, of course, the glucose gets worse. So I agree with Dr. Ballantyne. We really need to see completion of the data to get a better understanding. But I can't walk away from the, by chance, differences in the baseline use of 2 important antidiabetic medications and how over the long term they may affect glucose control, particularly if you're not making adjustments because you're in a Phase II trial.

Our next question comes from Prakhar Agarwal from Cantor Fitzgerald.

Can you hear me again?

Yes, we can.

Congrats on all the progress and congrats the team for the deal today. So maybe first one on APOC3 in sHTG. What doses are you thinking of taking forward on 25 milligram and 50 milligram? There is dose response on APOC3, but the dose response on non-HDL and HDL is less clear. And I had a couple of follow-ups.

Yes. We're just getting this data is partial, and we haven't made our mind about what dose to move forward, but your point is well taken. The 25- and the 50-milligram dose are very similar and overlapping most of the parameters. So that's the word that we're about to start to do now, do the appropriate assessment of the data modeling and simulation to come out with both the more appropriate dose for the population level.

Yes. And I was curious on the effect of ApoB in sHTG population. I know the mixed dyslipidemia population had reduction, but wasn't sure if the data was disclosed on sHTG.

We didn't have the data for this early data card. We have very few data, so that data will be presented when we complete this study at the end of the year. However, in the 1001 study, we did have a group of patients with severe hypertriglyceridemia. In that case, the base -- the cutoff was 300 milligrams, and we did see a 15% to 20% decrease in ApoB as well. So that effect was consistent across different patient population, at least for what we have from the 1001 study.

Again lastly, a question for Chris. In the context of implementation of Inflation Reduction Act, has there been any change in the strategy for some of the real indications like FCS, HoFH, for your CD portfolio?

No, there have been no changes. It's still too early to understand, I think, how that's going to play out over time. And so we're watching it, of course. So it has not affected our posture or our activities to date.

Our next question comes from Sahil Kazmi from B. Riley.

Can you hear me?

Yes.

Great. So the first one for Dr. Rosenson. On ANG3, given some of the disparate liver safety findings that we've seen across the different modalities, ASOs, siRNA and antibodies, I'm curious if you're aware of any other siRNA effort. And what might have been the learnings from those programs? Just to give that increased conviction that we have a sufficient safety database before these are advanced to Phase III trials.

Yes. So we were the global lead in the olpasiran study, the LPA study that was published in the New England Journal of Medicine, randomized about 41 subjects or 1 in 7 in the world. And it had extremely safe profile and no transaminase. This is really, I think, a difference between the ASO and then the RNA, although not all ASOs have had liver problems. I think that when you differentiate vupanorsen and ASO versus ARO-ANG3, you are seeing differences in the lipid responses, not in terms of the triglycerides, but the LDL cholesterol responses were quite disparate, which is saying that the ASO is targeting different aspect of the protein where you don't get the same endothelial lipase problems, I mean the inhibition, I mean same endothelial lipase inhibition. In terms of the safety, I think it's unclear, but recognized that the TIMI 70-TRANSLATE study, they use double the dose of the vupanorsen that they did in the earlier publication of fatty liver disease and diabetes that was published in the European Heart Journal, and it just brings up the issue as AKCEA was trying to push for more LDL cholesterol lowering. They were aware of our data from evinacumab with Regeneron, you got into a toxic effect. And I mean that's the best I can understand it on the published data right now.

Excellent. And maybe as a brief follow-up. Could you talk to what an ideal cardiovascular outcome trial design would be if it's ultimately required here given the profile we have? I know we've seen a few formats of these getting started with [ Orion and FORIA ] that are more focused on the LDL side. Then, of course, the all-pass-around story and some of the other obesity trials that are going on. Just curious kind of what your ideal design would be.

Well, I mean from my perspective, I think that the ARCHES-2 study population, where you're on maximum-tolerated statins here, have elevated triglycerides. Your LDL cholesterol is not a goal. Your non-HDL cholesterol is not a goal. It's a population that we really struggle with, and there are so many patients that fall into that category. If you offered them, let's say, a PCSK9 inhibitor, you'll lower the LDL cholesterol, but you're not going to be having much of an effect on triglycerides. We talked about the residual of triglyceride-related risk, which in large part is the remnant cholesterol, the TRLs. So I think it affords that opportunity. I don't know about the data on the glucose where this could be meaningful at the end of the -- upon the completion of the study. We didn't see that in the studies with the monoclonal. Certainly, it's different than an RNA. It wasn't really seen with the antisense. No significant changes in glucose. I just think you can't get away from some of these baseline differences the placebo group for. There's a whole other active groups. It's just one of these chance findings when you have a Phase II study that would balance out with larger numbers of individuals. But think about all the people in the United States that are obese, who have fatty liver disease, that have prediabetes, they have diabetes. This is a huge opportunity to find them a therapy that's going to take care of the multiple components of their atherogenic dyslipidemia profile. And that's, I think, a population that should be considered for an outcome trial.

Our final question comes from Patrick Trucchio from H.C. Wainwright.

I have a few follow-up questions. The first is just for either Dr. Ballantyne or Dr. Rosenson just in terms of FCS. The unmet medical need was characterized earlier in the presentation. I'm wondering what would need to be demonstrated in the Phase III program to support approval. And if you could frame for us based on the data that's been generated to date and the potential in this pivotal program, what proportion of FCS patients would you expect to be treated with APOC3, if it's approved?

I think all you have to do is show triglyceride reduction in the FCS population and safety. I mean, basically, you'd like to see some trends towards pancreatitis reduction. But then the FDA -- the EMA approved volanesorsen. The FDA -- the only reason they didn't approve it was the thrombocytopenia, which is the issues of side effects. The key issue is it is a manageable side effect. Thrombocytopenia can be dangerous, particularly patients who was not carefully followed because you can have bleeding disorders, including intracerebral hemorrhage. There's nothing in the safety profile here to suggest that there's going to be a problem. So I think it will be -- I think it can be pretty easy. And I think that you will see that most individuals who have it would want to be on treatment. It's very, very -- maintaining it -- Bob, you can talk about this. But we try to get people less than 10% fat diet. That is really a very difficult diet to do, and so the drinks aren't effective. So I do think you would have that, and you'd have -- as I said, I think there's a lot of people who have genetic disorders. They have heterozygous and they have a bad polygenic risk score. That's also, for me, and that's still a very small population, but it's substantially more than just pure FCS. It's still an orphan drug indication. But I think that they also -- personally, I think they should merit treatment too because it's still -- it's genetic, it's the menial. I think it's discriminating against them when they have a genetic disorder leads to severe high triglycerides, particularly if they have had a history of pancreatitis.

Yes, I agree with what Dr. Ballantyne said. The FCS population in particular is one that suffers typically from very young age, teenage age, young adulthood, and they're in the hospital frequently. And even though they can -- they may be able to restrict their diet, it still doesn't prevent every episode. And then you get into chronic pancreatitis. You could damage the beta cells in the pancreas. You get a very brittle type of diabetes picture, and it's just a horrible quality of life. I mean I'm really excited about the opportunity to help a lot of these patients that we see and suffer -- who suffer so often. I think the interesting discussion will be if you've got somebody who doesn't have FCS, do you use APOC3 or do you use ANGPTL3 inhibitor? And that, I think, will be the debate. Or do some of those patients who have non-FCS severe hypertriglyceridemia require both? As Dr. Ballantyne mentioned, those individuals without FCS, they have very high rates of coronary heart disease because they're carrying more -- I mean, there's -- these atherogenic lipoproteins, they just don't have chylomicrons, pure chylomicrons, which are too big to get into the arterial wall. But they've got chylomicrons and VLDL, which can contribute markedly to cholesterol loading in the macrophage. And of course, we talked about the pro-inflammatory and pro-thrombotic effects of these remnant lipoprotein. So I think that really becomes a debate in my mind, but FCS is clearly an APOC3 inhibitor.

Yes. That's helpful. And then just one additional follow-up for either Dr. Ballantyne or Dr. Rosenson. I'm wondering if you can comment on what you've seen from the efficacy, though, particularly from the safety profile of APOC3. And if the safety and tolerability demonstrated so far, including in this interim data presented today would indicate potential for regulatory approval of the compound in the more prevalent cardiovascular disease indication discussed earlier, where presumably a clean safety profile would be even more critical.

For CV indication, we're kind of going for -- obviously, the ultimate thing is what -- how much do you lower CV events? And someone asked me about, what would the trial design look like? It might look something like strength and reduce, except I don't see why you need to have an upper limit on triglycerides. Maybe taking out the people who are so severe, they're going to get pancreatitis early. You might cap it at 1,500 or something. I'm just throwing it out. This is not an Arrowhead idea. This is my idea. But obviously, you need to have -- those studies are larger, they're longer. And you need to look at all of the outcomes, MACE and mortality. So it's really hard to answer your question without knowing it. I mean statins lead to a slight increase in A1c. We use them all the time. They're very good agents. And they reduce events very well, and they have a great safety profile. So from what we've seen so far, this looks very good, but there's a lot of work ahead.

This is Javier. I want to iterate that we are very comfortable with the safety profile. I just -- and I mentioned that the SAEs that we saw in 2002, none of them are related to study drug, and there are things like knee surgery and COVID and [ uncontracted ]. So we're very comfortable with what we're seeing, and it's consistent with the Phase I study, and this will completely enable our Phase III study designs and interaction with the agency next year moving on to the Phase III studies.

This concludes our question-and-answer session. I'll now turn it back over to Chris for closing remarks.

Thanks, everyone, for joining us today, and thank you again to the speakers for an enlightening forum today.