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

Good afternoon, and welcome to Part 1 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. Next slide, please. So I'm just going to give a quick welcome and introduction. We've got a lot to cover, so we will be quick to get to the content. Next slide, please. So just reminding everybody that we will be making forward-looking statements today. So please refer to our regulatory filings for the risks to be considered in that regard. Next slide. So we've got a very good panel today. We're fortunate to have Dr. Christie Ballantyne, who is from the Baylor College of Medicine. He's the Chief of Cardiology and the Chief of Cardiovascular Research and the Director of Lipid Metabolism and Atherosclerosis Clinic Center for Cardiometabolic Disease Prevention. So again, we're very fortunate to have him. So thank you, Christie. From the company, Chris Anzalone, our President and CEO; Javier San Martin, our Chief Medical Officer; and Jim Hassard, our Chief Commercial Officer, will also be presenting today. Next slide. So we -- I'll just give a brief rundown of our pipeline and how we view cardiometabolic disease broadly. Jim will then talk about the market opportunity, specifically in cardiometabolic. Dr. Ballantyne will then talk about APOC3 as a therapeutic target and how it may address patient populations in hypertriglyceridemia. Javier will then talk about some of our clinical data, which we just presented last week actually at AHA and then our plans for clinical development for ARO-APOC3. And then Chris will give a wrap-up and explain why we're excited about that program. And then there'll be a short amount of time for Q&A. Next slide, please. So here is Arrowhead's pipeline, and we think that we have the broadest and most diverse pipeline in RNAi. We have drugs in development that are targeting various therapeutic areas, including cardiometabolic, pulmonary, liver, oncology and others. Shortly, we will also have drugs targeting muscle tissue. So not only do we have a good mix of early-, mid- and later-stage programs, we also have a good mix of both partnered and wholly owned, and you see that on the column on the right. And lastly, we are taking RNAi outside the liver. We have multiple programs in the clinic that are targeting liver express proteins. But importantly, we now have one drug and soon shortly multiple drugs targeting lung tissue as well as targeting tumors. And so we think that that's a big leap forward for the field and certainly an exciting area for us to create value for our shareholders. Today, specifically, we will be talking about the cardiometabolic programs. Next slide, please. So broadly, this is how we have viewed cardiometabolic. There's been a lot of progress made over the last couple of decades at reducing cardiovascular risk, mostly focused on LDL cholesterol. But there's still a good amount of risk for cardiovascular events and, frankly, for death for patients with cardiovascular disease. We see elevated triglycerides, persistently elevated LDL cholesterol and Lp(a) as kind of these 3 pillars of the next wave of cardiovascular drugs. And we have multiple programs targeting those 3 areas. We'll talk today about ARO-APOC3, which is mostly focused on the triglyceride side. Tomorrow, we'll be talking about ARO-ANG3, which gets to mixed dyslipidemia, so patients who are persistently elevated LDL cholesterol as well as elevated triglycerides. And then the bottom circle is Lp(a), which is -- we are approaching with our partner, Amgen. They have a drug called AMG 890, now called Olpasiran, which also presented their initial Phase I data at AHA last week, which looked very promising. So our strategy is to hit the residual risk that's still remaining. And we think -- we see the future of cardiovascular disease as more tailored to each patient's individual lipid parameters, especially as there's more tools out there to hit those various residual cardiovascular risk areas. Next slide. So I'll now turn it over to Jim Hassard, our Chief Commercial Officer, who will talk about those -- the patient -- or the market opportunity for those areas. Jim?

Thanks very much, Vince. Next slide, please. So why is important to continue to address cardiovascular disease despite the fact that statins and other interventions have been around for many, many years now? Well, first of all, there are an estimated 600,000 deaths per year in the United States alone, and this accounts for a projected $1.1 trillion in the future in 2035. And despite the fact that statins reduce the risk of cardiovascular death by 20% to 40%, for patients on statins, there is a 26% increase in the rate of major cardiovascular events if triglyceride levels are above 150 milligrams per deciliter. Next slide, please. So it is important, obviously, to address elevated triglycerides and elevated triglycerides come in at least 3 different disease types within cardiovascular field. First of all, familial chylomicronemia syndrome, or FCS, with a triglyceride level above 880 milligrams per deciliter, represents a rare disease with approximately 500 patients within the United States. However, there are no currently approved FDA therapies. And triglyceride reduction is obviously important, not only for cardiovascular risk, but also to reduce and prevent against pancreatitis. Secondly, severe hypertriglyceridemia, or with a triglyceride level above 500 milligrams per deciliter, currently is treated with fibrates and Vascepa. However, many patients do not achieve their triglyceride target. And so again, triglyceride reduction is important in this group of patients, again, in order to reduce the risk of pancreatitis and also cardiovascular risk. And then lastly, as represented by the previous slide, despite the fact that patients are on statins and possibly on fibrates or Vascepa, a triglyceride level above 150 milligrams per deciliter continues to be associated with cardiovascular risk. And so again, the opportunity to reduce triglycerides within this patient group is obviously important. Next slide, please. So when we look at the overall landscape of both elevated LDL and elevated triglycerides, this is what the picture looks like. On the far left side, when we look at elevated LDLs, clinicians have a number of interventions in which to use, including statins, PCSK9s and a number of evolving interventions are available to clinicians. However, at Arrowhead, what we try to do is look for unmet needs, unaddressed markets. Tomorrow, we'll discuss the area of mixed dyslipidemia. And again, in this area, there are interventions and combinations of interventions for clinicians to use, but there are very few single agent interventions. And we really feel that ARO-ANG3 is a single agent intervention for the future that clinicians can use to address mixed dyslipidemia. But today, we'd like to focus on, again, elevated triglycerides, and we'd like to discuss with you ARO-APOC3. And again, the disease areas here are, on the far right side, FCS, again, the highest triglyceride levels; again, a rare indication that ARO-APOC3 is uniquely characterized to address. Severe hypertriglyceridemia as well. And it moves over as well, there is an opportunity for ARO-APOC3 to reduce cardiovascular risk, again, in patients with triglyceride levels above 150 milligrams per deciliter. So to further discuss APOC3 as a therapeutic target, I'd like to introduce and welcome Dr. Christie Ballantyne. Dr. Ballantyne?

Okay. My video is still stopped. So -- and I can't open it. Here we go. All right. Next slide, please. So triglycerides. This has been a very interesting and exciting change in our approach for both lipids and cardiovascular disease. We've been focused on LDL cholesterol for decades. And there was a big focus on HDL cholesterol, but that has now shifted towards triglycerides and a lot of it has become -- is because of basically genetic epidemiology. Now we've known that triglycerides and triglyceride receptor proteins were associated with cardiovascular disease, but genetics has led us to some very big insights and particularly APOC3. We knew plasma APOC3 levels predicted coronary heart disease, and we'll talk a bit more. Then there were discovery of APOC3 loss of function mutations. These reduce plasma lipoproteins. They reduced cardiovascular disease also. And this led to a focus on basically as soon as you find a loss of function variant, now you jump into approaches towards doing this with biotechnology. And this was first already looked at with an antisense and now we have sRNA. Now what we've seen is that if you target people with -- we know that APOC3 plays a critical role in lipolysis. But it turns out there's LPL-dependent and independent pathways, is that basically when you inhibit APOC3 is that both of these pathways, you can even people with FCS who completely lack lipoprotein lipase. So they basically homozygous for mutations in LPL, this approach still works. So that's really interesting. But let's -- next slide, let's take a step backwards in terms of the importance of triglycerides in heart disease. Now people have known for a long time, this was some work that was done by the Patsch brothers, Josef and Wolfgang Patsch, in the late '80s and the '90s. They were studying postprandial lipemia. We've known that people who have heart disease have an increase in triglycerides, they have lower levels of HDL cholesterol, and we'll kind of get to -- how those are related. And we measure lipids in the fasting state. So when you go to get your lipids checked, typically, it's after a 12-hour fast. What does that mean? That's the best your triglycerides are going to be for the entire day. Now as shown here on slide, if you look at this on the left-hand side, the people with heart disease, after a fatty meal, their triglycerides go up higher and they stay up longer. Now why is that important? Well, what time did you eat breakfast this morning? So let's say if you ate breakfast at 7 o'clock, what time is lunch going to be? Well, 5 or 6 hours later. Look when the peak is here for the person with heart disease. So they get the first fat load, they go to McDonald's and eat breakfast, and they go -- their second fat load is at lunchtime. And that's going to get them another 6 hours until when? Dinner. So how do you spend your day? Most people, you've got 18, 19 and depends if you snack at night, but you've got maybe 20 hours a day in a postprandial state. That is actually where people live, in the postprandial state. So that -- what with the Patsch brothers had said that, well, we know in the postprandial state, you have these increased levels of triglyceride receptor proteins that all contain apoB, they're atherogenic and that this is the real culprit in regards to -- and particularly, what have we seen is the epidemic our society, obesity, insulin resistance and diabetes. Next slide. So a big breakthrough came when they were looking at the Amish. And let's go to the next slide. It turns out they were giving the Amish a fat load, a high-fat meal, and they're looking at basically what -- postprandial lipemia. And they noted that there was a mutation which led to a -- look at the diminution of the triglycerides in the postprandial state. This is for people who are heterozygous. So a 50% deficiency. Next slide. What did it do? Well, the APOC3 levels were reduced 50%. That you would expect. There was a decrease both in the fasting and the postprandial triglycerides and also a decrease in non-HDL cholesterol, LDL cholesterol, VLDL cholesterol, IDL cholesterol, HDL cholesterol went up. All the lipoproteins changed and they had lower coronary calcium scores, less atherosclerosis. So after this, we're done. The other trials which showed the APOC3 loss of function brands were associated with fewer myocardial infarctions also. Let's go to the next slide. So how does this all fit together? Well, it turns out that most individuals, when you were -- what we see is the epidemic of our society is basically obesity and insulin resistance with diabetes, you end up -- is overproducing, basically, VLDL. And then you have these increased VLDL particles in your circulation. These are the triglycerides particles. And they are -- not only are they -- you make too much, but they are slowly catabolized, so they hang around a long time. And they're interacting with LDL particles and HDL particles. So what you end up with is less -- lower levels of HDL cholesterol due to CETP's action and also small dense LDL. So this is a highly atherogenic profile. But the focus had been on HDL measure -- remember, we measure lipids in their fasting state. Triglycerides bounced around a lot. So people that focus on HDL cholesterol as the target, it turns out, HDL cholesterol is probably the marker of people with postprandial lipemia. If you look at glucose in epidemiological studies, it's not very predictive, but hemoglobin A1c does predict heart disease because it tells you what happens over a long period of time. And the Patsch brothers, 30 years ago, said that HDL cholesterol was simply a marker for people who have bad postprandial lipemia, and the real culprit is these atherogenic VLDL remnants, IDL and the small dense LDL particles, although HDL is altered and the function of HDL may also be altered here due to the changes in composition. Next slide. So let's go to the spectrum of problems. FCS is very rare. However, I have a few FCS patients, and it's really difficult because nothing works. You have to be on a diet of less than 10% fat. If you have one bad meal, you see what ends up happening here, how those numbers went up. So one bad meal and someone can end up with sky-high triglycerides. If they had a bad weekend, they end up in a hospital with pancreatitis. So having a new therapy would be life-changing for these individuals. This would be -- certainly qualifies as an orphan drug. Now what happens more commonly is people just have a high triglyceride. And why do we worry about a triglyceride of 500? Remember, that's measured in the fasting state, 500 or 600. What happens in the postprandial state? Well, I already showed you, your numbers can easily double. So somebody could go out and eat a big fatty meal and then if you drink some alcohol with it, so the experiment that happens every Friday night in Houston, people go out and they have Mexican food, and they'll get the fried chips with it, then have enchiladas and refried beans, have a few cervezas and margaritas, you can jack up your triglycerides from 600 or 700, go way up in the 1,500, 2,000, if you have one bad meal, even a bad weekend on top of it, and then end up in the hospital with pancreatitis. Now they also have -- as I mentioned, there's increased risk for cardiovascular disease, which is the other aspect of this. But triglycerides were neglected for a long period of time. It turns out that the genetic epidemiology has clearly shown that if we look at the variance associated with higher triglycerides, they have more disease; lower triglycerides, less disease. And so this has really turned into a central focus, not only for the severe cases, but also better understanding cardiovascular disease. Next slide. I think that's the end of -- so yes, this was basically, these people, really, we have a -- we have some therapies, which had some benefit. Nothing for FCS. We have some medications. But even with all the medications we have, Omega 3s, fibrates and statins, it's still a lot of people who we're just not able to treat them well. Next slide. And I think that's the last item. Turn this over to Javier.

Thank you, Dr. Ballantyne. Next slide, please. As Dr. Ballantyne said, APOC3 is key regulator of triglyceride-rich lipo proteins and as such, is a good candidate target to treat patients with severe hypertriglyceridemia. So that's the first population that we're focused on. And we define that as patient with 500 milligrams per deciliter of triglycerides fasting all high. Those patients are in excess with -- for pancreatitis. And as he said, the goal of therapy is decrease triglycerides below that threshold of 500 that typically is associated with a much less frequency of pancreatitis or acute pancreatis. Next slide. So ARO-APOC3 is an RNAi that silence the APOC3 gene and by that, means decrease the synthesis of the protein APOC3, the content of that in chylomicrons and TRLs in general. By doing this, the reduction in APOC3 enable LPL-dependent and independent pathway to clearance TRLs, and at the same time, increase remnant clearance by the liver. The combination of these 2 effect are the reason why we see a significant decrease in TRLs and remnants. So let me now shift to the clinical data that was recently presented. Next slide. This 1001 is our first-in-human study that has a Phase I component and a Phase IIa component. The single dose in normal healthy volunteers and multiple dose in healthy volunteers was already presented, so we'll focus today on the patients with high triglycerides as defined with 300 milligrams per deciliter higher on patient with chylomicronemia defined as TG graded at 880. This patient received a baseline dose and then a dose at day 29, and we follow them until day 113. And then patients switch over to an extension study. Primary endpoint was safety, pharmacokinetics and pharmacodynamic. And with this next slide, please. Based on characteristics of the population, we have in the high triglyceride population of 4 different cohorts at doses of 10, 25, 50 and 100 milligrams. The chylomicronemia cohort, which is 16 patients and did not have a placebo group were dosed at 50 milligrams, all of them. BMI across the goal, on the high side, as expected. You see the APOC3 level and triglycerides based on the inclusion criteria was elevated in all cohorts. But I want to notice that the people who have higher level of TG, which is the 25 milligram in the HTG population and the chylomicronemia cohort, have higher level of APOC3 conceived. Next slide. This is the pharmacodynamic result. On the top of the slide, you see the HTG population. APOC3 without this reduced by about 80% to 99% with all 4 doses. And as a consequence, you see the decrease in triglycerides level somewhere between 75% and 90%; again, doses from 10 to 100 milligrams. The bottom of this slide is to the chylomicronemia patients, again, very consistent results. APOC3 decreased by about 96% and triglycerides level of 88%. So despite the baseline characteristics, both population behave very similar. Next slide. Again, the same profile, HTG patient with regard to non-HDL cholesterol. We observe a 40% to 60% reduction, and HDL cholesterol increased by about 100% in average with all 4 doses. Chylomicronemia patients with a, again, very similar with about 60% reduction in non-HDL and about 120% increase in HDL cholesterol. Next slide. Safety profile is shown here. The more frequent AE was injection site reactions, all the case were mild. And the second more frequent event is the elevation of ALT. All cases were transient and asymptomatic and returned back to baseline by the end of the observation period, 113 days. There was the highest case of increase in ALT in a patient with history of cholelithiasis and biliary colic. The baseline ALT was 22, and the elevation went up to 230 at day 85, returning back to baseline at the end of the study, and this subject subsequently underwent elective cholecystectomy treatment. No clinical significant adverse event with regard to platelets, bilirubin and creatinine. No drug discontinuation and 1 SAE of pancreatitis in patient with history of pancreatitis. Next slide. So in summary, in patients with hypertriglyceridemia are doses from 10 to 100 milligrams subcutaneously [ during a baseline ] in 1 month showed a robust and sustained reduction in triglycerides, non-HDL and an increase in HDL. The level of decreases in APOC3 range from 80% to 99%; triglycerides, 74% to 92%; and non-HDL have decreased from 40% to 60%, with a very significant increase in HDL. The results from the chylomicronemia population of 50-milligram dose was essentially very similar to those observed in the HTG population. So this effect was sustained, as showed before, up to 12 weeks and we are waiting for more information as we move forward. The safety profile has supported the latest case development. Next slide. And this is how the next step development looks like. The first Phase III study will be in patients with FCS. We aim to enroll about 60 patients. The primary endpoint is TG, but we're going to describe the risk of the PD. The second study is a Phase II dose-finding study in a population with severe hypertriglyceridemia defined as greater than 500 milligrams per deciliter. We will enroll about 300 patients in 3 dose groups. And again, the same primary endpoint, TG, but we're going to offset the number of secondary TG parameters and of course, pancreatitis as a exploratory endpoint. This study will enable a Phase III study of about 900 individuals, again, with the same patient population and triglyceride being the primary endpoint. Also, we're planning a Phase II study dose finding in patients with hypertriglyceridemia between 150 and 500 milligrams to eventually -- this study might enable a cardiovascular study in at one point. With this, I will give this over to Chris Anzalone. Chris?

Okay. Thanks very much. Thank you to Dr. Ballantyne, of course, for sharing your thoughts on this important program for us. Thank you, of course, to Vince and to Javier and to Jim for putting this on. And of course, thank you to all of you who are watching the webinar here. This is -- it's really our pleasure to talk about this program. We think it's an important program, and we're excited about what we might have to offer to patients in the near future. Next slide. Okay. So with ARO-APOC3, we see a compelling market opportunity. There is substantial cardiovascular risk driven by Lp(a) triglycerides. I think that the data have been clear in recent years on that. APOC3 is a validated target for hypertriglyceridemia. We know the loss of function mutations in APOC3 are associated with lower triglycerides and decreased cardiovascular disease risk. The competitive landscape that we will be entering is attractive to us. ARO-APOC3 is the only RNAi candidate currently in clinical development against this target. So it leaves us with antisense oligos and fish oils as the primary competition at this point. ARO-APOC3 has shown substantially lower -- substantially better triglyceride lowering effects than fish oils. So we feel good about that competition. Then with respect to antisense oligos, we don't expect to see the ASO-related safety issues that have been shown in the past, such as thrombocytopenia. In addition, we expect dosing schedule advantages. We expect ARO-APOC3 to have good durability and enable dosing every 4 to 6 months versus a monthly dosing of an antisense oligo. Next slide. So where do we go from here? As Javier talked about, we have near-term clinical plans for ARO-APOC3. Beginning in the first half of 2021, we plan on starting a Phase III study in FCS patients. We also plan on starting a Phase IIb study in severe hypertriglyceridemic patients. These are those with triglycerides above 500. That will enable us to move forward into a Phase III study following that Phase IIb. And we also plan on starting a Phase IIb study in patients with triglycerides above 150. That gives us optionality. I don't know if we will move into a Phase III study in that population, but it gives us the ability to do that should the data suggest that we have something to offer for those patients. And this clinical plan allows us a staged commercial approach. We intend to address the FCS population relatively quickly. There is a severe unmet medical need for these FCS patients, as described by Javier and by Dr. Ballantyne. We then expect to expand this into the about 4 million patient population in the U.S. alone that suffer from severe hypertriglyceridemia. Again, these are those folks with triglycerides above 500, and we think we have something important to offer those patients. And then again, we will have the optionality of reaching down once again into the above 150 range of triglycerides should the data appear to support that. So this is our plan right now. Again, it is a pleasure to talk about this. This program is moving reasonably rapidly and will make, I think, big leaps forward in the first half of next year towards our ultimate commercial goal here. And with that, next slide, I will open the call up to questions.

Thanks, Chris. So Sara, our first question comes from Mayank Mamtani from B. Riley FBR. I think he's still muted. Okay. So next question is from Swapnil Malekar from Jefferies.

Vince, can you hear me?

Yes.

This is Swapnil on for Maury Raycroft at Jefferies. So I had one question for Dr. Ballantyne. So although you touched a little bit about this, but for patients with hypertriglyceridemia, LDL cholesterol levels can be misleading. So the measurement for non-HDL cholesterol, which potentially reflects the atherogenenotic (sic) [ atherogenic ] particles. So what are your thoughts on those 2 as the biomarkers? And with the data seen from APOC3 -- ARO-APOC3, are those reductions sufficient to address clinical outcomes in patients?

So yes, I agree with you that what ends up happening when people have elevated triglycerides is the LDL cholesterol level is deceptive. It's lower than you think it is. And that non-HDL cholesterol is a much better marker. So these reductions in non-HDL cholesterol of 40% to 50%, in fact, are very impressive. Now with a statin, what ends up happening is you always -- if your LDL reduction is 50%, your non-HDL cholesterol reduction is less than that, it's more like 40%. We published this years ago, looking at all the statin trials because you lower LDL better than you do VLDL. So this -- if you're thinking about this strategy fitting on top of generic statins, it's exactly complementary with it. But I think the non-HDL cholesterol is the parameter to look at. And that is why I think that there's great promise for here, not just for only severe high triglycerides, but also for the people who have this mixed hyperlipidemia pattern. And it may end up being that HDL cholesterol is also a good biomarker for the person who has problems with postprandial lipemia. Rather than actually doing a postprandial test, you can just look at -- well, if their TGs are up and their HDLs are low, there's a large number of South Asians who have this problem very commonly. So I think it's got a lot of promise.

Okay. And like what -- any thoughts on the data that is seen from ARO-APOC3? And like what do you interpret in terms of clinical outcomes?

Well, so one thing that's kind of nice having been through multiple programs over the years with statins, and I was very much involved with the omega-3 programs, but to have something where you can get an agent into the clinic for severe patients so that particularly physicians get some feel for how well does this drug work. And as you saw, it worked extremely well for lowering triglycerides. The effects on non-HDL cholesterol are also very impressive. HDL goes up, and it goes up for the right reason. This is not the same as a CETP inhibitor. This is by basically the impact on postprandial lipemia. So I think what you will see is that the physicians who already have been using this would be very looking forward to what will be the next step, can this work for cardiovascular. Because it looks like it should, but they would already be using the agent, which makes uptake so much easier and faster with it. The other point is this dosing of every -- that we don't know if it's -- I guess, we saw 3 months good efficacy and if it's every 4 to 6 months, particularly for people who have had pancreatitis, the patient who has obesity, high triglycerides, the ones who tend to get into trouble the most are people who occasionally forget their medicines. And although you would say, well, how can somebody forget their medicines or people forget their diets? It's just -- I mean, it turns out it's -- I'm fairly obsessive-compulsive -- well, many people would say I'm very obsessive-compulsive, but I would say moderate. But I use a pill box because I take medications. I have a bad family history. So I take medications twice a day for blood pressure and lipids. And there's not a week that goes by where I don't forget at least one dose, at least one dose every week, and that's -- so it's just... In clinic, we see this all the time. Somebody comes in, their numbers bounce way up. And it's a very unforgiving disorder. So if you can get an injection every 4 months or 6 months, and that keeps that down, that is really a -- for these particular patients, that is a major, major plus. And I think the antisense is looking very nice also, about once a month versus every 4 months, that could even be just -- go to the doctor's office, get your injection and you're taken care of with it. So that's a -- it's a patient-friendly, clinician-friendly option.

Okay. And one question for the Arrowhead team, if I may. So are there any gating factors before you initiate the Phase III trial in FCS? And like what are the doses? Are you saying what doses will be used for that particular cohort?

Chris, do you want to take that? And then Javier, you can take [indiscernible].

Javier, why don't you go ahead and take that?

Yes. So we are working on our IND preparation. We are set to initiate both, probably the FCS Phase III and the Phase II in severe hypertriglyceridemia in the first half of this coming year. We are considering to test the 3 lowest doses in the severe hypertriglyceridemia Phase IIb study. So you saw the data and really between 50 and 100, there is no difference. So 50 will be the highest dose that we will test in both populations.

Thank you. And our -- we can take the -- go back to Mayank Mamtani from B. Riley FBR. I think he is live now.

Can you guys hear me now?

Yes.

Okay. Great. And congrats on the update. So maybe if I can pick on the prior question on the dose here for the 2 Phase IIb study. Could you speak to why not go higher? And if there's any feedback you might have had from the regulators on that given the data that you've generated. And then I have a follow-up for Dr. Ballantyne.

Yes. Well, as I already showed, that you see very little dose response when you go from 25 to 100. So you always try to go with the lowest dose that achieve the best possible effectiveness results, and we believe that the dose is likely to be somewhere between 25 and 30 or 1 of those 2. So we're confident about that. We have not discussed with the agency the dose. We're working on an IND, but we did have interactions about this program. And like I said, we're working as we speak to file an IND very soon.

Great. And then on the HTG population specifically. I was just curious, Dr. Ballantyne, really helpful to hear from you on the fasting and the perennial triglyceride levels. I was just curious, recent triglyceride lowering therapy trials, for certain reasons, and it could be lifestyle modification or clinical trial execution, the placebo responses are pretty high. So could you maybe comment on why that might be and really thinking about implications to doing a cardiovascular outcome study as a result of that?

So the placebo response -- and we're probably talking about -- where we've got into some issues is when you have an omega-3 preparation, which is in oil, how do you pick a placebo? And there's controversy about using mineral oil, which is really light paraffin oil being potentially adverse, it turns out that corn oil and olive oil actually have some favorable impact on triglycerides. And then the issue is if you have a capsule, I know they try to use, I think, cellulose with water and one of the more recent ones with another triglyceride approach in the placebo group went down a lot. So it is -- there is the potential of those. Now this -- these are -- in this case, it's an injection and then the injection then frequently. And as you do a little longer-term studies, there's also -- when people go into a trial, they tend to get motivated. And there -- may be more likely when they're being seen frequently initially on, there's some changes sometimes in diet and exercise. And triglycerides are very much influenced by lifestyle changes. So it is something -- there is -- these are not the easiest trials to do. With FCS patients, they're quite extreme and very high. So -- but when you're seeing a difference of 25%, you may have problems. When you're seeing a difference of 85% to 90%, that's easy to see with it -- even with that variability. So I think part of it has to do with the -- there are some challenges with it. The longer the duration of the study, the more likely that initial enthusiasm wears off. But also having an agent where you really make a profound reduction in triglyceride, obviously, is much easier to test statistically.

Any comments on the outcome study EP ?

Who are you asking?

I think he's asking...

I mean, I guess, Vince, maybe this question can go to you. So how do you think about the Phase IIb data that would be generated between severe and HTG levels or triglyceride level above 150? And how does your Gannt chart look like for 2021, 2020, where you'll start making those decisions? And what sort of things you need to see as proof of concept? That was my final question, Vince -- or Chris, excuse me.

Sure, I'll take that. So let's see, how do you answer that? So look, the usefulness of ARO-APOC3 to the FCS population in the severe hypertriglyceridemia population above 500 seems clear to us. We think we've got a very good chance of really helping these people. If you look at our data, as Dr. Ballantyne said, we're not looking at 20% to 25% improvement, we're looking at 80% to 90% improvement in triglyceride levels in those patients. And that's life changing, right? That's talking about moving these people into the normal range. That's a big thing. That's not around the margins. So we know we're going to do that. We have confidence that, that Phase III study in FCS population will be -- we are optimistic that it will be helpful, and we're optimistic about the severe hypertriglyceridemics. When you look at -- when you reach down to those patients above 150, it's less clear. There's a lot more going on there. And so I wouldn't put parameters around our Phase IIb study and around those data at this point. I think we do the study and let's see what it looks like. We are optimistic that we'll see good improvements in triglyceride levels, but let's see what those look like, and we'll go from there.

I'll make one comment, I'm the outsider here, but is that when you have a drug that's on the market, it gives you also another, I would say, it's not a luxury, really. It's the opportunity that you can have a little smaller trial with longer duration. And this is not a trivial issue. If we take a look at what Amgen did is they made a -- they were -- they wanted to get this result so fast to really open -- they shortened the duration of that study, and they very much hurt in terms of the things that the health care plans look at the number needed to treat is absolute event reduction. And many people don't even calculate how long the study was. I mean it's simplistic, but what they look at is absolute event reduction. So if you take a high-risk population and you make it a full 5 years of follow-up, but you can do -- if you have a drug that's already actively being utilized, it's -- the statin trials all -- the statins were all approved for use, so they could do 5-year studies. When people are trying to get into the market and can't get there, they rush these studies and they haven't had as robust and it hurts eventually. But I think having a clear indication, which, as you said, these massive reductions, the other trials take longer and they're a little bit more -- you take some more patients to do it. And if you can figure out a way to have a smaller sample size, that would be beneficial, too, with it. But it's -- I think it's a great advantage to be able to have something that's being used because it gives you the luxury to look a little longer, design it better and then let it go longer because you already have a commercial product.

Yes. Amen on that.

As an Amgen ex-insider, I absolutely appreciate that. And makes sense to take time and do the right study rather than rushing it.

And let me just underline a part of that. What's so attractive to us about certainly, the FCS population, but maybe more importantly, the severe hypertriglyceridemic population is it's a large population. We think there's about 4 million of those patients in the United States right now. We think we can get to market relatively quickly with that population because we think that showing triglyceride lowering is an approvable endpoint, if history is a guide. That allows us to get to market and to start enabling physicians to treat those patients with this drug relatively soon, and then we can see what this looks like over time.

Next question is from Madhu Kumar at Baird.

Yes, can you guys hear me?