Okay. So, it's my pleasure to introduce our next guest from Arrowhead, Vince Anzalone, the VP of Finance and Investor Relations. So Vince, welcome. Thank you for joining us today, and maybe just to start, maybe give us a brief overview of the state of the business for Arrowhead and your accomplishments year-to-date. Sure, and thank you so much to you, Ken, and to the entire Chardan team for having us today. So we have come a long way as a company. You're talking about the 2024, you know, I wanna go back a few years and just kind of level set about who Arrowhead is, what the strategy is for the company, what we've done recently to accomplish that strategy, and kind of where we're going over the next few years. So as everyone knows, we're an RNAi platform company. So we use the RNA interference mechanism to silence genes associated with disease, not necessarily disease-causing genes, but associated with disease. Historically, the field has been focused on liver-expressed genes. We are leading the field in bringing RNAi outside the liver into many different cell types throughout the body. We now have the ability to target hepatocytes, obviously, muscle, lung, and adipose tissue coming up, and others in the future, and it looks very, very good, and I think that the benefit of targeting multiple tissue types is that you can address the diverse disease areas that have been historically undruggable. The challenge with that is that our pipeline is enormous, and it's growing over the coming years, which is again, the good side is that we have a diversified pipeline and portfolio. The challenge is we need to be able to focus in certain areas. And so recently, we've been very focused on fully resourcing plozasiran, which is our lead drug against hypertriglyceridemia, which I know we'll talk about in a moment. And somewhere around 75% or so of our R&D spend is focused on ploran, which has just completed our first phase III and started three additional phase III studies, which we'll read out in a couple of years. We plan to launch that drug next year in a narrow population, and now we're building out commercial to support that, as well. So, you know, going back, the platform part of the business continues to expand. So we're addressing many different cell types and many different disease areas. And what's emerging now, and which, you know, your original question about twenty twenty-four, is the commercial side of Arrowhead. And that's a new thing for us, and I think that's a big step for any growing biotech company, the ability not only to make the technology work and to make the clinical studies have positive readouts, but actually to make a business out of these drugs and to get medicines into physicians and to patients who need them, and bring in commercial revenue. You know, that's the... That is the end goal for any successful product. So what we've done this year is we have... We presented data and published data several different times on our cardiometabolic pipeline. Plozasiran, we'll focus on mostly today. We've had positive phase II readouts in two different patient populations, in patients with severe hypertriglyceridemia, or SHTG, and patients with mixed hyperlipidemia, and ASCVD driven by that mixed hyperlipidemia. We also had a phase III readout in the PALISADE study, which we just presented at the European Society of Cardiology meeting a few weeks back and published in New England Journal of Medicine, and the data just looked fantastic. Again, we can talk about those in a moment, but that drug is really gonna be the fuel for our commercial build-out. Again, we'll be launching next year in a narrow population, and then growing that drug into multiple different progressively larger patient populations over the years after that. And so I think, again, we've done a lot of work on the early stage programs, on the platform development, and now the late-stage development and commercialization is starting to become the focus. Great. So I'm glad you talked about the fact that you've been around a while, and because of that, you have a very broad and deep pipeline, which is frankly a good problem to have. Yet your valuation doesn't seem to reflect that. You know, when we talk to investors, you know, they're always concerned about, you know, given the cash burn, "If I invest now, am I gonna get diluted in six months or whatever?" So, talk to me, at least from a strategic point of view, how you guys are trying to balance all the opportunities that you have in front of you, that you clearly have evidence that your pipeline could support successful development in, with the fact that you don't have unlimited cash, so you've got to sort of pick and choose, you know, where to spend your time and invest your dollars. Sure. Yeah, I think there's two sides of that. So there's one, the balance sheet side, you know, how are we gonna access capital? And then two, kind of the P&L side, the expense side of that question. So starting with the balance sheet, if you look back over the last six or seven years or so, we've brought in about $1 billion in cash in business development, not, you know, biobucks, but actual cash in the door through business development. We've done equity somewhere around $700 million or $750 million. We've done debt $400 million, and we've done about $300 million in kind of structured or royalty monetization. So it's a lot. It's a lot of cash. The important part is that we are spreading out the sources of capital. I think that's the smart strategy over the long term, 'cause you can't really, you know, you can't predict the future, so we don't know what's gonna be the lowest cost source of capital, so we wanna spread it out. However, the largest single source of capital has been business development, and as you mentioned, and as I mentioned earlier, the growing pipeline gives us a lot more opportunities to do business development. And so it's on us. You know, we need to get more business development deals over the finish line to do two things. Again, the balance sheet side of it, we need cash in the door, but also it reduces the growth in our R&D spend in the future, to put programs in the hands of pharma or somebody else, who's gonna maximize the value of the asset. That's been our long-term strategy. I would say over the next six or some odd years, it will be a similar strategy. The good thing now is that as we're approaching commercialization for our lead product, and as partner programs and our own programs get to that commercialization point, we're no longer solving for an unlimited amount of capital that we need. You know, there's a number of years in the future that we predict that we will be cash flow positive and that we'll no longer have to, you know, seek as much outside capital as we had historically. Yeah, 'cause I mean, let me ask you this question: is it an execution story? We're telling the story better because one could certainly make the argument. I've actually made the argument that you know, Dicerna was bought a few years ago, $3.2 billion. Let's say they had a dozen candidates in the clinic. You've got 12, 14, when we think about the total portfolio right now, later stage, and your valuation is lower than where they were taken out at. So from your point of view, is it executing on the story or being able to tell the story better so people understand what you have and where you're going? Yes and yes. I would say both of those are true. It's always hard to make a comparison, you know, for historical M&A transactions because that was a point in time with a portfolio at that point in time with pharma interest and pharma cost of capital at that point in time. But, you know, you're I agree with your sentiment completely, and obviously I'm biased here, but I feel like we are ridiculously undervalued with all of the different assets and opportunities that we have. And I'd like to focus on, you know, plizaseran after this because the data continued to look fantastic, but even outside of plizaseran, you know, we have generated some really compelling data for products that just have, excuse me, a whole lot of commercial potential and clinical potential, and for any biotech company, that's if you start with the products, excuse me, if you start with good products, with good data, with addressable markets, with limited competition, everything else flows back from that. So that I think we have succeeded in a very big way. You know, we are enormously productive at discovering and doing early development for high-value programs. We need to move those on through clinical development and find a commercial outlet for all of those, but that's an execution story, as you mentioned. But the, you know, I think that in this environment, it's hard to do work on Arrowhead because there are so many programs to analyze and diverse therapeutic areas. If investors want focused exposure to one therapeutic area or one candidate, it's just not... you know, it's hard to do that with Arrowhead. And so I think that, you know, your second point about the message, you know, we could do a better job at focusing the story around what we think is the nearest term opportunities for value, and plizaseran, I think, is at the center of that story. Let's talk about the data for plizaseran. Yeah. So, you know, obviously, most recently, we saw the detailed results from the PALISADE phase 3 at ESC. It's very good data, and maybe just to tee that up, talk about the characterization you did for the drug in SHASTA 2, and then that's led to really your approach of it's a pipeline and a product. Sure. So what's really attractive for us, excuse me, about plizaseran is that it's one gene target, APOC3, but it's multiple diseases that it might have applicability in, going from ultra rare, which is FCS or familial chylomicronemia syndrome, all the way to the highest prevalence of atherosclerotic cardiovascular disease. You know, so you're looking at a patient population on the rare side, which is a thousand patients or so in the US, all the way up to, you know, twenty plus million patients on the highest prevalence side. We are approaching that in kind of a staged way, both clinically and commercially. The initial phase III readout that we had was in FCS, and we define FCS in a different way than just genetically. So we enrolled patients in that study. It was seventy-five or so patients. It was about evenly split between genetically confirmed FCS, so patients who harbor a specific genetic mutation that's called familial chylomicronemia syndrome. And then, the other half of the patients were ones that had the exact same clinical syndrome, so had the same disease, but didn't have that genetic signature. So it could be that they have a genetic mutation that's not known or polygenic mutations that causes the same disease. And this is a disease that limits people's ability to metabolize and clear triglycerides, so they just build up in the bloodstream. So a normal triglyceride level is a hundred and fifty mgs per deciliter. These are patients where the mean baseline was two thousand. Some of these had, you know, multiples of that. So these are patients whose blood, you put it in a centrifuge and spin it down, and it, you know, separates out and looks like cream. It's just heavy, thick with triglycerides and triglyceride-rich lipoproteins. The clinical manifestation of that disease is that these patients have very limited diets, and lifestyles are severely impaired. They have this kind of brain fog and persistent abdominal pain, and then the most severe get acute bouts of pancreatitis that can lead to hospitalization and sometimes death. And so it's a very undertreated disease that really causes a very poor quality of life, and there are no drugs approved in the U.S. to treat specifically FCS, so physicians are really in need of new therapies. The data from our PALISADE study show that we can reduce triglycerides by 80% from baseline in both populations. So we did an analysis of genetic versus clinically confirmed, and it's basically the same. You know, if you look at both of the doses we tested together, one of them was more active in one population, and the other dose was less active in that population. So on balance, it's basically the same reduction. So we shouldn't be limited just to a genetically confirmed population, which potentially expands the addressable market for FCS. The second thing that we saw, other than triglyceride lowering, is that we had a durable response. So when we dosed these patients once every three months, we didn't get these wild swings in triglycerides. It was within a month, it was down to the bottom, and over the year when they were on therapy, it basically stayed down that 80% or so range. Which is important for a disease like this, where if they get spikes, that's when they can... That's when that acute pancreatitis can become, you know, a big issue. And last, we showed a statistically significant reduction in the risk and occurrence of acute pancreatitis in patients on drug versus placebo. We reduced pancreatitis events by 83%, and we're the only drug in a clinical study to show a statistical significant result with respect to that measure. And so I think we... You know, not only did we tick all the boxes, but the data just... They really look fantastic. You know, you mentioned ESC. We had a good team out at ESC talking with physicians. And not only just for FCS, but broadly for SHTG, and then down the road, cardiovascular disease. There's a lot more appreciation for the role of triglycerides in those three different disease areas, and it's getting a lot more attention with physicians. I don't think, you know, investors have gotten to that same point yet. The triglyceride market for new medicines has been somewhat challenging in the past, and I think, you know, it's the, you know, a couple reasons, but the primary reason in our mind is that there haven't been really effective drugs at reducing triglycerides to the extent that plozasiran can. You know, if we're talking about 60 to 80 to more reduction from baseline in triglycerides, that moves the needle in every different patient population, and so I think that SHTG opportunity, which we haven't talked about yet, is really an underappreciated market opportunity that I think investors will start to get smart on. You know, based on the data we saw at ESC, we think you're well positioned to get approval. As far as the label, based on your conversations with the FDA before you started the study and the results you saw in both patient populations, do you think that's sufficient to be able to get that broader label? I wouldn't put words in FDA's mouth ever. I think that's a... You know, it's very challenging to predict what your label is gonna look like. We haven't, you know, we haven't filed the NDA yet, but our plan is to file before the end of this year. But historically, the FDA tends to give you a label that is consistent with the patient population you studied. And again, we did study genetic and clinically confirmed FCS, but again, we, you know, we have to have those discussions with FDA and see where the label comes out. Okay, so you've advanced the drug into the SHTG phase III studies, SHASTA 3 and 4. You also plan on doing SHASTA 5, again, addressing the acute pancreatitis. So answer two questions. One, how much larger was that patient population for SHTG? How impactful would a positive result in SHASTA 5 be, both in terms of your competitive position, the view of payers for your drug? So talk about those ramifications. Sure. So the first, the size of that opportunity, so SHTG is, you know, characterized by trigs above fasting triglycerides above 500 mg per deciliter, and it's a spectrum. You know, the lower end of that is probably larger, or a larger number, but the higher end is a more severe disease. So when you're getting patients to the 800 or even above 800, it's. There's a lot higher willingness to treat for physicians. And they're somewhere in the three to four million or so patients in the US with trigs above 500, so it's large, it's sizable. The SHASTA 3 and SHASTA 4 studies, between the two, they're basically the exact same design, just two separate phase III studies, but between the two, we're somewhere in, I believe it's 700 or 800 patients total. The primary endpoint for that study is just reducing triglycerides at a year, and that's the approvable endpoint. And we think that that will be sufficient for commercial payers in the US. Now, different payers will have a different view of it, but we think, you know, on balance, commercial payers in the US will give us coverage with just triglyceride lowering. Again, the higher end of that SHTG spectrum, there'll be more patients that would be on drug than on the lower end, but I think that coverage. We're confident that we'll have good access. Ex-US, in Europe and then in other geographies, it'll be a bit more challenging, and that'll be kind of a country by country decision. There are certainly significant economic markets where just triglyceride lowering will likely get access. There's others where we think that we need to show a clinical benefit or a longer term kind of hard outcome, and for this disease, acute pancreatitis is that kind of harder clinical outcome. So the SHASTA5 study is. I'm trying to remember the exact number. It's somewhere between 100 and 150 patients total. That's not time-bound. That's an event-driven study, similar to a cardiovascular outcome study, but with pancreatitis being the outcome. So patients will be on drug until a sufficient number of events happen on the placebo side, and then we'll be able to assess the separation for treated versus placebo. We think that outcome is gonna be very helpful with certain national payers, to show the value of the product. Again, I think it'll be a country by country kind of discussion that we have to have. Well, let's focus a little bit on your second focus area, which is lung. And going back to the early part of our discussion, you guys have been at this a while, and when you've been at something for a while in drug development, not everything's gonna work. But what you have shown as a company is you learn from your mistakes and you get better. So we saw that with DPC. That led to the evolution of TRiM, which has produced a number of very good drugs. A drug candidate, I should say, since, you know, they're on their way to being approved? Almost. Almost. So similarly for the lung, ARO-ENAC, your first-generation product, you know, had some tox issues. So what did you learn from that, and how did you impart those learnings into your three second-generation lung candidates? Right. That was... You're right, that was a big learning for us, and that's the challenge with development stage biotech, certainly for platform companies, is you don't know how preclinical results are gonna translate to humans until you know, until you do the experiments. And so our first generation lung delivery, with our first generation candidate, ARO-ENAC, was trying to treat CF, cystic fibrosis. What we found in preclinical toxicology studies is that there was. We were just giving too much drug. There was this macrophage overload syndrome, which caused local lung inflammation at chronic dosing. We didn't see anything in humans, in the single or multiple dose study. This was just a preclinical toxicology finding, but it led us to the realization that we needed to get better on potency and duration, so both of those things needed to change. So we needed to give less drug, and we needed to give it less frequently, in order to get over that kind of macrophage overload syndrome issue. And so with our new generation candidates, ARO-RAGE, ARO-MMP7, and ARO-MUC5AC, they have, you know, varying degrees of potency, but all are multiples of what we were giving for the ARO-ENAC program. And so we have done chronic toxicology studies for MMP7 and for RAGE, and we think we have a wide therapeutic window, and that we've gotten over that hump. So, for example, with ARO-RAGE, the comparison with ARO-ENAC is really stark. We were giving, for ARO-ENAC, we were dosing on three consecutive days every two to three weeks. With ARO-RAGE, we're giving a single dose likely every two months. One dose every two months. It's just dramatically different exposure, because it's a dramatically more active drug with a much longer duration of response. And so if you think about the patient population in asthma, you know, that's a very patient-friendly dosing regimen. You know, it's something that's gonna be very helpful with adherence and compliance, and something that, you know, this population and other lung disease populations are used to doing, which is nebulizing, but it's not a daily nebulization, it's a once every two months nebulization. So I think that was a big learning from us. We knew what we had to get over, and I think we've gotten over that. And now it's a process of not only showing can we translate preclinical results into humans, but, you know, now it would be at phase two, showing that if we inhibit those targets that we've selected, is there gonna be a clinical downstream benefit? Is there efficacy here? I think we've shown activity. The next step is to show efficacy in patients. Okay, so just maybe as a final question, remind us of the timeline to see the data from the lung programs, RAGE, MUC5AC, and MMP7? MUC5AC and MMP7 will likely have initial target engagement data, you know, call it in a matter of months, say. You know, maybe end of the year or give or take. With RAGE, we've pretty much characterized target engagement, both in healthy volunteers and in patients with mild asthma. So I think that we've shown the drug can do what it's designed to do, and the next step would be, are there any signals of an anti-inflammatory effect? Or more importantly, in a traditional phase two study in asthma, are you reducing exacerbations and, you know, does it work in asthma? That readout is gonna be a bit down the road, you know, 'cause that would require a, you know, a real honest-to-goodness phase two study, not just a quick and dirty assessment of activity. But I think that, you know, we've gotten a good amount of validation for the platform. For RAGE, in particular, we've shown that the drug can get a high level of target engagement. We've reduced the expression of RAGE in the lung by 90% or so. And so now it's really a matter of doing, you know, midstage studies to show if we have a, you know, a commercially attractive product. Okay. Well, we've reached the end of our time here. I know we could spend a lot more time talking about the rest of your programs, but thank you so much for joining us today. Thank you. Thanks so much.