Good morning, everyone, and welcome to part one of Arrowhead Pharmaceuticals' 2026 summer series of R&D webinars. At this time, all attendees are in a listen-only mode, and a question- and- answer session will follow the formal presentations. If you'd like to submit a question, please use the Q&A text box at the bottom of the webcast player. 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. Thank you, Tara, and thanks everyone for joining us today. This is the first installment of our 2026 summer series of R&D webinars. Today's session will be focused on our cardiometabolic pipeline. Later in the summer, we'll also detail our obesity programs and our new CNS programs, including our tau program targeting [Alzheimer]. Before we start, just want to make sure you know that we will be making forward-looking statements today, so please refer to all the risk factors in our SEC filings. Okay, here's the basic agenda today. I'll give an overview of the cardiometabolic pipeline. James Hamilton, our Head of R&D and Chief Medical Officer, will talk about our technology and the process that we use to discover and develop new drugs. Dr. Jennifer Hellawell, our Head of Clinical Development in Cardiometabolic, will talk about plozasiran and zodasiran, specifically the clinical development programs. James will come back and talk about our first dual-functional siRNA, which we call ARO-DIMER-PA, which silences PCSK9 and the APOC3 gene. Dr. Steve Nissen from the Cleveland Clinic will talk about the mixed hyperlipidemia market and the treatment landscape for ASCVD. At the end, we'll also have some time available for Q&A. Before we start, I just want to introduce Dr. Nissen from Cleveland Clinic. He's the Chief Academic Officer for the Heart and Vascular Institute at Cleveland Clinic. It was very hard to put his bio into one page because he has a long and storied career, and we're very fortunate to have him with us today. He has been involved with or has directed pretty much most, if not all, of the large cardiovascular outcome studies over the last couple of decades. This is not an overstatement that I think he is insight personified when you're talking about cardiovascular disease. Thank you, Dr. Nissen, for joining us today. Okay, quick overview about Arrowhead. As most of you, I'm sure know, we're an RNAi therapeutics platform company. We have our own independent products, as well as partnered programs. They're all based on a proprietary platform that we call Targeted RNAi Molecule or TRiM. We launched our first commercial product last year as REDEMPLO, which is approved to reduce TGs in patients with familial chylomicronemia syndrome. It's now approved for that indication in the U.S., the EU, Canada, Australia, and China. We think that that product by itself has a multibillion-dollar opportunity across the multiple indications over the coming years. Importantly, we see the potential for multiple independent and partnered launches over the coming years. Our pipeline already today is extremely broad. We have 20+ clinical stage programs. Most of those are wholly owned. We also have a good mix of early, mid, as well as late-stage programs, so it's a very diverse pipeline. Our first approved indication was a very rare disease, but we don't have a slant towards rare disease. We are aiming to treat diseases that are both rare and ultra-high prevalence, which you'll hear about later today when we talk about mixed hyperlipidemia and ASCVD. There's probably 20 million patients with that condition in the U.S., and our pipeline is growing. We aim to have two to three new clinical programs every year that we generate with our technology. As I mentioned before, everything is built on the Targeted RNA Molecule or TRiM platform. It's designed for deep and durable gene silencing. Importantly, we think Arrowhead is the clear leader in the field at bringing RNAi therapeutics to diseases outside the liver. As James will talk about, we can now access seven different cell types in the body with our technology. Lastly, we have extremely strong balance sheet, and we are funded now into potentially multiple commercial launches, again, both independently and with partners. We expect additional non-dilutive capital over the coming years to come in from our existing partnerships with Madrigal, Sarepta, Amgen, Takeda, GSK, Novartis, and Royalty Pharma. We are in a very solid and stable position as a company. Here is a diagram that talks about where we are looking to play with our cardiometabolic pipeline. If you think about this diagram, on the left side, it represents elevated LDL cholesterol. The further left you go, the more severely elevated that is. On the right side, it's elevated TGs or triglycerides. Again, the further to the right you go, the more severely elevated they are. For the right side of this diagram is FCS. Patients with TGs that are in the thousands that are at very high risk of acute pancreatitis. For those patients, as I mentioned, we have an approved therapy called REDEMPLO, and it's approved to reduce TGs in patients with FCS. As you go a little bit more to the left on this diagram is severe hypertriglyceridemia, patients with TGs above 500 that are at a heightened risk of acute pancreatitis. As Jen will talk about later, we have a phase III program that should be reading out in Q3 to potentially address that population. On the left side, as you go all the way to the left, is Homozygous Familial Hypercholesterolemia, or people who have LDL cholesterol above 400 that get early onset cardiovascular disease, and again, that's also very rare. As you go more towards the middle is the intersection of elevated LDL and TGs or the mixed hyperlipidemia population. These are patients who have elevated triglyceride-rich lipoproteins, remnant cholesterol, LDL, and TGs. For that middle part of the population or mixed hyperlipidemia, we have the ARO-DIMER-PA, the PCSK9 ApoC-3 dimer. We're trying to play in all different parts of this LDL-TG spectrum. Here's a diagram of what we hope will happen in the future, and obviously this is forward-looking. We have our first launched product in REDEMPLO on the bottom left. It was approved to reduce TGs for patients with FCS in 2025. Pending successful clinical data and regulatory review and submission, we hope our next launch independent will be for sHTG with the plozasiran or REDEMPLO product in 2027. In 2028, we hope to launch zodasiran, again, pending successful clinical development and regulatory review for HoFH, and that is scheduled or hopefully anticipated for 2028. Beyond that, we have the ASCVD programs, and the obesity programs, which we'll talk about later. Down in the bottom right, we also have a late-stage partnered program with Amgen called olpasiran, which is in phase III development for cardiovascular disease associated with elevated Lp or Lipoprotein. Let me turn it back over to James and he'll talk about Arrowhead's technology and R&D process. All right. Thanks, Vince. Just to reiterate, for those who are new to the story, Arrowhead is an siRNA company and we don't do anything else. Everything's focused on developing siRNA drug molecules. All of our drugs are derived from a platform we call TRiM or targeted RNAi molecule. What is TRiM? The platform is really, at its core, an aggregation of rules, algorithms, and internal know-how, enabling optimal siRNA sequence selection and molecule design. Our goal is to maximize on-target potency while reducing or totally eliminating any risk of off-target gene silencing. We combine our sequence selection acumen with a library of different targeting ligands and linker chemistries designed to facilitate delivery to various cell types. Importantly, this platform is modular, so once a delivery system has been validated, the process for developing new sequences against new targets using the same delivery platform can be repeated over and over. This allows for rapid progression from new target ID to first-in-human proof of concept. One of the strategic differences between Arrowhead and other siRNA companies is that we decided early on to push the delivery technology outside of the liver. Arrowhead's very good at designing so-called GalNAc molecules, and we have many liver-targeted siRNAs, including REDEMPLO, which has been approved in the U.S. and in Europe for familial chylomicronemia syndrome. However, our clinically tested and increasingly clinically validated extrahepatic delivery technology is broader than the delivery capabilities available to any competing ASO or siRNA company. This includes, of course, hepatocyte delivery, as well as a clinically validated platform for delivering to pulmonary epithelial cells, and separate platforms delivering to skeletal muscle, adipocytes, and the CNS, all currently in clinical trials. I'll add that the CNS platform uses subcutaneous delivery rather than an intrathecal route of administration used by many of our competitors. Importantly, we continue to innovate. We've been working on preclinical platforms for delivering siRNA to the eye, both the back of the eye as well as the anterior chamber of the eye, also to cardiomyocytes, as well as several other cell types. This breadth of platform capabilities supports one of the most productive R&D discovery engines in biopharma. The evidence for this is our expansive pipeline, which represents 20 novel molecules in various stages of clinical development and is diversified across stages of development, disease indication, as well as a mix of partnered versus wholly owned assets. Importantly, this is our pipeline since 2016 when we had zero drugs in the clinic. We've been averaging a little better than two INDs or CTAs for new molecular entities per year over the last 10 years. Again, all of our programs are homegrown. We've not in-licensed any molecules from academia or other companies. These have all been derived from the TRiM platform. Just to provide some additional details on discovery platform productivity, we average initiation of about 10 new discovery programs per year, which leads to about four new clinical lead nominations annually. Naturally, there's some attrition. We aim for an average two to three new INDs or CTAs per year, and our goal is to go from new target ID to a CTA in 12 months or less. Now, as I've described, Arrowhead has done extensive delivery platform development work, but one of our biggest challenges is maintaining a steady stream of good new targets where we can apply the TRiM platform to develop siRNAs against those targets. Historically, new targets may have originated from KOL panel discussions, literature searches, or competitive intelligence. However, recently, we've increased our investment in using AI capabilities to analyze the large amount of genetic data generated by overlying target cell expression patterns with a variety of human genetic databases to identify new targets ideal for siRNA therapeutics. This is a data-dense approach which has been successfully amplified using various AI engines to facilitate new target ID qualification and assessment. While we're relative newcomers to developing internal human genetics discovery capabilities, we anticipate increased investment in this area to ensure a steady supply of new gene targets. I'd now like to shift gears and hand things over to Dr. Jen Hellawell, who will review our late-stage progress and future plans with plozasiran and zodasiran. Thank you, James. Hypertriglyceridemia represents a spectrum of disease with severe clinical manifestations and considerable unmet need across that spectrum. Later today, Dr. Nissen will describe the unmet need in patients with moderate hypertriglyceridemia, generally triglycerides in the range of greater than 150 mg- 200 mg per deciliter, a condition affecting upwards of 10 million people in the U.S. with substantial atherosclerosis burden and overlap with other cardiometabolic risk factors. However, severe hypertriglyceridemia, defined as a serum triglyceride level of greater than 500 mg per deciliter, affects approximately one in 100 persons or over 3 million people in the United States, and can have similarly dire clinical consequences, including an increased risk of life-threatening acute pancreatitis. Much like atherosclerosis, risk in these patients with severe hypertriglyceridemia is driven primarily by both higher levels of the causal lipoprotein, in this case, triglycerides, and a history of prior clinical events, in this case, acute pancreatitis. For this reason, patients with the highest triglycerides and prior acute pancreatitis events are often referred to as high-risk severe hypertriglyceridemia, and this subset is thought to represent about one in 1 million people in the United States. Of course, at the very top of this spectrum is, or bottom of the spectrum on the slide here, is the most severe and rare form of hypertriglyceridemia, known as familial chylomicronemia syndrome. This is a genetically inherited condition which can be diagnosed through identification of biallelic recessive pathogenic variants or through established clinical criteria. This condition affects potentially 6,500 to over 10,000 people. It's characterized by triglycerides persistently in the chylomicronemic range, which is usually described as greater than 880 mg per deciliter or 10 millimoles. These patients have an extremely high risk of acute pancreatitis, with many patients with FCS suffering multiple recurrent attacks and a variety of related severe sequelae throughout their lifetimes. Unfortunately, as we know, conventional triglyceride-lowering therapies such as fibrates and omega-3 fatty acids rely primarily on fully functional lipoprotein lipase pathways which are often dysfunctional in these patients and therefore often have very modest effects on triglyceride levels. Importantly, until very recently, none have been shown to reduce the risk of acute pancreatitis. Apolipoprotein C3, or ApoC3, is a key lipoprotein involved in triglyceride hydrolysis and clearance through both lipoprotein lipase-dependent and independent pathways and has recently emerged as a therapeutic target across the full spectrum of hypertriglyceridemic disorders. The SUMMIT program was built around the therapeutic hypothesis that plozasiran, a silencing RNA targeting ApoC3, can facilitate triglyceride clearance through de-repression of lipoprotein lipase and increased hepatic uptake of triglyceride-rich lipoprotein remnants. The phase III PALISADE study demonstrated that plozasiran can effectively decrease circulating triglycerides in FCS and thereby reduce the risk of acute pancreatitis in that population. As Vince mentioned earlier, these data served as the basis for the approval of plozasiran or REDEMPLO for the treatment of adults with FCS in the U.S., China, Australia, Canada, and the European Union. In addition, prior randomized phase II-B trials, SHASTA-2 and MUIR, established short-term efficacy and safety of plozasiran in severe hypertriglyceridemia and moderate hypertriglyceridemia. However, up until recently, the long-term durability and safety data in these particular populations have been limited. A few months ago, we shared data from the two-year open label extension of SHASTA-2 and MUIR evaluating the long-term efficacy, safety, and tolerability of plozasiran 25 mg dosed quarterly across the mild to severe hypertriglyceridemic populations. A total of 418 patients were enrolled in this two-year open label extension with approximately 250 and 170 patients from the MUIR and SHASTA-2 parent studies respectively. Participants initially received open label plozasiran administered every 12 or 24 weeks at the assigned dose level of the parent study until a final dose of 25 mg quarterly was selected over the remaining two-year follow-up period. The primary objective of the study was to assess safety, though, of course, secondary endpoints, including change in fasting triglycerides, ApoC3 levels, non-HDLC, and a variety of other lipoproteins were assessed. Baseline characteristics of this open label extension were similar to those of the respective parent studies. Of note, in considering the generalizability of these findings to the broader severe hypertriglyceridemia population, we can see that in the SHASTA-2 subset of the open label extension, baseline median triglycerides were between 680 mg-730 mg per deciliter, and roughly one in five or 20% of patients had a prior history of acute pancreatitis. Consistent with observations in the parent studies, plozasiran induced robust, consistent, and clinically meaningful reductions in triglycerides throughout up to two years of follow-up in the open label extension. During the open label extension, median triglycerides continued to fall by 82% and 83% at month 12 and month 24, respectively, while mean triglycerides reduced by approximately 77% and 79% at month 12 and month 24, respectively. In terms of the clinical meaning of these effects, in the SHASTA-2 subset, about 94% of patients achieved fasting triglycerides less than 500 mg per deciliter, which is the well-established risk threshold for increased risk of acute pancreatitis. About 63% achieved fasting triglycerides less than 150 mg per deciliter, which is considered the upper limit of normal. This was at month 12. Moreover, 96% and 63% of patients maintained these clinical thresholds throughout the entire 24 months of follow-up. In the MUIR subset, plozasiran treatment was associated with median reductions in triglycerides relative to baseline of 67% at both month 12 and month 24, and mean triglyceride reductions of 62% and 63% at months 12 and 24 of the open label extension. Consistent with these robust and sustained triglyceride reductions, there was a reduction of acute pancreatitis events as well, with no acute pancreatitis events occurring in both studies during the open label extension. As a reminder, in the double-blind period of SHASTA-2, in the parent study, three episodes of acute pancreatitis occurred during the randomized period in two of 61 patients in the placebo group and one episode in 165 patients receiving plozasiran 50 mg, translating to an odds ratio of 0.18. Though considering the small size of the study and short follow-up, the 95% confidence interval did cross one. In the open label extension, however, overall, 11 events were sent for adjudication by our abdominal events adjudication committee, and of these, zero were positively adjudicated for acute pancreatitis referencing the Atlanta criteria. The extrapolated curve represented above by the dotted line shows the expected results if participants who had been initially assigned to placebo had continued receiving placebo in the open label extension. Finally, plozasiran demonstrated a reassuring long-term safety and tolerability profile consistent with index studies. We saw stable glycemic parameters and no clinically meaningful changes in liver or renal function, as well as no new safety signals that had not previously been detected. In conclusion, in our combined open label extension of the phase II SHASTA-2 and MUIR studies, long-term treatment with 25 mg quarterly of plozasiran resulted in sustained and clinically meaningful reductions in triglycerides across a broad spectrum of hypertriglyceridemia, including severe and mixed phenotypes through up to two years. This provides critical insights into what the longer-term effects of plozasiran will look like in this broader population. The majority of patients in the open label achieved triglyceride levels below clinically relevant thresholds for acute pancreatitis, and many achieved levels below what's considered the upper limit of normal with 96% of severe hypertriglyceridemia patients achieving triglycerides less than 500 mg per deciliter and 63% of severe hypertriglyceridemia patients achieving levels less than 150 mg per deciliter. There was a reduction in acute pancreatitis events, with no adjudicated acute pancreatitis events occurring in both studies in the open label, which implies that longer-term treatment with plozasiran further reduces the risk of the clinical outcome of interest, acute pancreatitis. Importantly, plozasiran demonstrated a consistent long-term safety and tolerability profile as I previously described. Therefore, with a better understanding of the long-term safety and efficacy of plozasiran in severe hypertriglyceridemia from this open label extension, we very eagerly await completion of our SHASTA-3 and SHASTA-4 studies. As previously discussed, these two pivotal double-blind, placebo-controlled phase III studies were designed to meet regulatory requirements for substantial evidence of effectiveness to evaluate the efficacy and safety of plozasiran in adults with severe hypertriglyceridemia. After screening patients with severe hypertriglyceridemia, which was defined as fasting triglycerides greater than 500 mg per deciliter and meeting other key eligibility criteria described here, were randomized to plozasiran 25 mg dosed quarterly for one year versus placebo to match. The primary endpoint of both studies is percent change in fasting serum triglyceride levels from baseline to month 12, followed by a number of key secondary endpoints described here on the slide. Of course, we're assessing adjudicated acute pancreatitis events from day one to month 12, and frequency and severity of adverse events and serious adverse events over time through month 12. The two studies completed enrollment about a year ago at a total of 351 sites across 23 countries. Ultimately, 757 patients were randomized with 446 and 311 in the SHASTA-3 and SHASTA-4 studies respectively. Consistent with the known epidemiology of severe hypertriglyceridemia, the mean age at enrollment in these studies was in the early 1950s. Roughly 80% of patients were male and predominantly white. About 1/3 of patients were enrolled in North America, less than half in the EU member states, and about a quarter were enrolled in Asia or elsewhere. The enrolled population did indeed have the expected features of metabolic syndrome with a mean BMI around 31, 62% having diabetes at baseline, and about 2/3 also having hypertension at baseline. Given the high burden of these comorbid conditions, it's not surprising to see that that translated into considerable polypharmacy with almost reporting taking at least two medications, 69% being on statins, about 61% on fibrates, though we acknowledge the limitations of those agents in this disease state earlier. Also consistent with our understanding of this disease, there was quite a bit of variability in TG levels or triglyceride levels at baseline, with mean triglycerides at screening of 966 and at randomization of 863. Again, looking at medical history at baseline, there was a high prevalence of metabolic syndrome, but also, a high prevalence of prior history of acute pancreatitis, with 20% of patients having had at least one episode prior to screening and randomization. Having completed enrollment a year ago, we continue to target top-line data release for the SHASTA program in the third quarter of this year. This timeline should support presentation at a medical congress and publication of the results in the second half of this year. Finally, a supplemental NDA filing by the end of 2026. Turning now to another cornerstone of our late-stage cardiometabolic pipeline, I am also pleased to provide some updates on our zodasiran development program. To understand zodasiran and our development program, we need to appreciate the disease state of homozygous familial hypercholesterolemia, which is a rare inherited lipid disorder characterized by extremely elevated LDL-C in the range of 400 mg-1,000 mg per deciliter. That is about 10 times normal levels. We know that left untreated, people with this disease develop atherosclerosis, severe aortic stenosis, as teenagers, sometimes even in early childhood, in infancy. Homozygous familial hypercholesterolemia is considered an orphan disease with estimated prevalence of about one in 300,000 people worldwide. Although the armamentarium of safe and effective therapeutics for HoFH continues to grow, unfortunately, HoFH patients often have suboptimal responses to conventional lipid-lowering therapies due to their dysfunctional LDL receptor pathways. Highlighting this unmet need, a 2023 report from the CASCADE FH Registry, which is a registry overseen by the Family Heart Foundation and draws from data on over 80 million Americans. Data from this registry revealed that over 3/4 of adults and 44% of children with HoFH in the U.S. already had documented atherosclerosis or ASCVD at the time of clinical ascertainment. Furthermore, despite treatment with three, sometimes six lipid-lowering therapies concomitantly in specialty clinics around the U.S., just a quarter and 32% of adults and children reach their LDL-C goals. Shockingly, despite their well-recognized atherosclerosis and ASCVD risk profile, over half of the patients in the HoFH registry were on no lipid-lowering therapies. Unfortunately, many of these same trends were also reported in a recent report from just last month from the Global HICC Registry, which is the world's largest HoFH registry of almost 1,000 patients from 45 countries. All these data highlight that not only is there an ongoing need for availability and access to safe and effective therapies for HoFH, but also for treatment regimens to which patients can readily adhere, given the considerable polypharmacy. Therapies targeting angiopoietin-like 3, or ANGPTL3, thankfully offer new promise for HoFH patients. ANGPTL3 is a hepatocyte-expressed regulator of lipid and lipoprotein metabolism with multiple potential modes of action depicted in this schematic here, including inhibition of lipoprotein lipase, or LPL, and endothelial lipase, or EL. Within roughly the past decade, more and more data has emerged to show that ANGPTL3 loss-of-function genetic variants lead to enhanced LPL and EL activity, thereby resulting in substantial lifelong decreases in circulating LDL-C and other atherogenic lipoproteins, driving a decreased lifetime risk of ASCVD. Importantly, there is no known adverse phenotype associated with this genetic deficiency. The mechanism of ANGPTL3 is independent of the LDL receptor pathway, therefore highlighting its promise as a therapeutic target in HoFH. The VISTA program was built around the therapeutic hypothesis that zodasiran, a silencing RNA against ANGPTL3, can facilitate both LDL-C and triglyceride reductions through mechanisms orthogonal to those of conventional lipid-lowering therapies. That is, through combined de-repression of both LPL and endothelial lipase. In this development program, we observed consistent reductions in ANGPTL3 levels of up to 96%, triglycerides of up to 71%, and LDL-C of up to 50%, along with other lipid parameters across a variety of patient populations studied. Zodasiran, across these studies, has shown a reassuring safety profile with no changes in platelets, modest non-progressive signals of worsening hyperglycemia, and no severe signals of hepatic or renal toxicity thus far. GATEWAY was an open-label, randomized phase II study designed to evaluate the efficacy and safety of zodasiran, our liver-targeted RNAi therapeutic, in patients with HoFH. The study was conducted at seven clinical sites across the world, patients aged 16 years or older with documented HoFH who are receiving stable lipid-lowering therapy and were on stable diet at baseline, who had a screening LDL cholesterol of greater than 100 mg per deciliter and triglycerides less than 300 mg per deciliter were randomized in a one-to-one fashion to receive zodasiran 200 mg or 300 mg on day one and month three. The study ultimately enrolled 18 patients with mean baseline LDL concentrations of 9.8 millimoles, which translates to about 380 mg per deciliter, despite being on background lipid-lowering therapy. At month six, patients showed substantial dose-responsive reductions in fasting LDL-C, with means of about -36% and -40% in the 200 mg and 300-mg dose groups respective. This was consistent with what we had previously reported in interim results. Following partial washout, all patients entered into the open-label extension in which zodasiran showed continued evidence of effect with reductions in fasting LDL-C of about 40% observed for an additional 12 months. There were no drug discontinuations or drug-related SAEs, severe adverse events, or deaths. The overall safety and tolerability of zodasiran was quite reassuring and consistent with what had been previously noted in other studies. These promising results informed the design of our ongoing YOSEMITE study, which is a phase III study to evaluate the efficacy and safety of zodasiran or ARO-ANG3 in both adolescents and adults with HoFH. This study is currently enrolling eligible adult and adolescent patients with HoFH, which can be defined by either genetic confirmation or established clinical criteria. Upon completion of the 12-month double-blind treatment period, patients are offered the opportunity to continue on into an open-label extension. After screening, eligible patients are randomized two to one to zodasiran 200 mg dose at day one, then quarterly after a loading dose at month one, versus placebo to match. The primary endpoint is percent change from baseline to month 12 in fasting LDL-C levels, followed by a number of key secondary endpoints, which are designed to assess the effect of zodasiran across a variety of other lipoproteins of interest, as well as safety, as assessed by incidence and severity of treatment-emergent adverse events. The study is nearing completion at a total of 47 sites across 21 countries worldwide. Ultimately, we are targeting enrollment of 60 patients worldwide. As YOSEMITE completes enrollment, we are simultaneously pleased to report the launch of a broader pediatric program in HoFH, beginning with our SPRUCE study, which is a phase III single-arm open-label study designed to evaluate the efficacy and safety of zodasiran in adolescents with HoFH. This study shares many design features with the YOSEMITE study and aims to randomize its first patient later this summer. We believe that successful execution of this study could then pave the way for subsequent pivotal studies in younger age groups. To recap, while we eagerly await top-line data from our SHASTA-3 and SHASTA-4 programs of plozasiran in severe hypertriglyceridemia, we continue to make strides in our VISTA development program of zodasiran in HoFH. YOSEMITE is expected to complete enrollment any day now, and completion of the 12 months double-blind portion of the study would be expected in summer 2027, which would hopefully support our first new drug application for zodasiran in the second half of 2027. Now I'm pleased to hand it back to Dr. Hamilton to discuss ARO-DIMER-PA. Thanks, Jen. Another area of successful innovation at Arrowhead has been in the development of siRNA dimer or dual functional technology. This involves the linkage of two siRNA sequences, each against a different gene target, allowing the targeted silencing of two genes with a single molecule. While our most advanced iteration of the dimer technology uses the GalNAc-ASGPR targeting delivery to hepatocytes, we are working on dimers for a variety of different extrahepatic cell types. For our first dimer, we wanted to pick two targets that made sense medically to combine and that were well-validated. We think that combining siRNAs targeting PCSK9 and APOC3 make a lot of sense as an approach to potentially treat patients with mixed hyperlipidemia, with the goal of reducing their overall atherogenic particle burden. APOC3 is a key regulator of triglyceride metabolism and a validated target for lowering remnant cholesterol. Similarly, PCSK9 is a key regulator of LDL receptor recycling and a validated target for reducing LDL cholesterol. Importantly, in the mixed hyperlipidemia patient population, there should be an additive effect when it comes to reducing circulating atherogenic lipoproteins, which we can assess by tracking changes in total ApoB as well as changes in LDL cholesterol and remnant cholesterol. We've shown some encouraging initial data in monkeys with our ApoC3-PCSK9 targeted dimer, where PCSK9 and ApoC3 knockdown were achieved with magnitudes comparable to the individual monomer treatments, and these data have been presented previously. Also previously presented in spontaneously dyslipidemic monkeys, reduction in PCSK9 and ApoC3 translated as expected into reductions in non-HDL cholesterol, LDL cholesterol, and triglycerides of approximately 50%. The dimer program has progressed into phase I. This is a single and multiple escalating dose study in patients with mixed hyperlipidemia. There's no healthy volunteer component to this study. All cohorts require participants to have baseline triglycerides of 150 mg- 499 mg per deciliter, as well as either non-HDL greater than 100 or LDL greater than 70 mg per deciliter at baseline. In terms of progress, we should have single escalating dose cohorts fully enrolled by mid to late summer and full study enrollment completed by the end of the third quarter. We still anticipate sharing some top-line data sometime in the third quarter. I'll now turn things over to Dr. Steve Nissen from the Cleveland Clinic, who will provide more details on the mixed hyperlipidemia patient population. Steve? Thank you very much, James. Really appreciate the opportunity to join you and discuss this, I think, very innovative approach to targeting two lipid abnormalities with a single molecule. Let me talk about mixed hyperlipidemia, but first let me introduce myself. I'm the Chief Academic Officer of the Heart, Vascular & Thoracic Institute at the Cleveland Clinic. I'm a preventive cardiologist. I've been involved in clinical trials for a number of years. What is mixed hyperlipidemia? Well, it's really pretty simple. It's a simultaneous elevation of LDL cholesterol and triglycerides, often accompanied by reduced HDL cholesterol. It's distinct from isolated hypercholesterolemia or isolated hypertriglyceridemia because it requires both. Importantly, the clinical hallmark is an increased number of circulating ApoB-containing particles, that is the atherogenic particles that are involved with both of these abnormalities. The Venn diagram shows you that there's a group of people that have elevated LDL cholesterol, a group of people that have elevated triglycerides, quite a substantial overlap group that have both abnormalities in daily practice. We talk about the atherogenic lipid triad, and that's triglyceride-rich remnants that's accompanied by small, dense LDL, that's a more atherogenic form of LDL cholesterol, and low HDL, which also appears to amplify risk. There are some common drivers, including insulin resistance, metabolic syndrome, hepatic VLDL overproduction, but very importantly, highlighted here is impaired lipoprotein lipase clearance, which you've heard from Jen Hellawell, it's something being targeted by plozasiran and zodasiran, that leads to the atherogenic lipid triad. How common is this? Well, if you take hypercholesterolemia, total cholesterol greater than 240, triglycerides greater than 200, we're talking about in excess of 10 million U.S. adults that have each of those conditions with, again, substantial overlap. There was a study done by NHANES. This is this very large study being done by the federal government in patients with lipid disorders. What you see is that it's common amongst all groups, but highest in Mexican Americans, a little bit less likely in Blacks. You can see in gold, hypercholesterolemia, in blue, hypertriglyceridemia, and their frequencies of distribution in the NHANES cohort. There is, in fact, a genetic disorder here that we term familial combined hyperlipidemia that's different from FCS. This is a polygenic lipid disorder. This represents about 0.3%-0.4% of the population. Genetically driven, not driven by presence of either diabetes or obesity or any other drivers. Even though it's only 0.3%-0.4% of the population, that's about 1.3 million people that have this disorder. You will see clusters in families of this syndrome. The really key observation here is how prevalent this is in people with coronary heart disease, shown at the right, with MI survivors and all MI survivors. Something like 40% will have familial combined hyperlipidemia. It really does lead to a lot of cardiovascular morbidity and mortality. Now, hard to treat. If you look at residual ASCVD risk despite statin therapy, 48% of our population, not at LDL-C goal, 38% have high triglycerides, and 26% have low HDL. This comes from a very large study done in statin-treated patients. In these patients, really LDL control is not sufficient, and here's why. Even with intensive statin therapy, the five-year risk of major vascular events exceeds 20% in patients with established coronary heart disease. Residual risk has not gone away, and a lot of that risk you could attribute to the triglyceride-rich remnant lipoproteins and low HDL that statins do not fully address. Of course, as you've heard from others on this call today, there is a pancreatitis risk. For triglycerides above 500, approximately 1% risk, at 1,000, a 5% risk, and at 1,771, a 16% risk. I do see these patients referred to us. They're really quite needy patients who have had, in many cases, episodes of acute pancreatitis, sometimes more than a dozen episodes over a long period of time. Now, we have great treatments for LDL cholesterol, we're not getting there. Unfortunately, this is a shocking slide, in people with an LDL cholesterol greater than 190 mg per deciliter, at least a quarter of them in recent periods of time are both untreated and unaware. If you include the people that are aware but not sufficiently treated, it's a lot of people that we just aren't getting to goal. Where is Arrowhead heading with this DIMER program? Well PCSK9, validated target. APOC3, now a validated target. Validated for the case of PCSK9 with drugs like inclisiran. That's an siRNA for PCSK9, approved. APOC3 targeting, drugs like plozasiran, also validated. That we clearly have two targets that we have an approach for treatment. We are hoping to be able to get simultaneous and durable reductions in LDL cholesterol in the range of 50% and triglycerides in the range of 70% or even greater with this DIMER, with this dual targeted siRNA, with relatively infrequent injections, perhaps four times a year. That enhances adherence. Adherence is an enormous problem in treating these patients. The good news is that tolerability for small interfering RNAs has been excellent. We now have a number of them approved. They have very few AEs, generally just minor injection site reactions, a very well-tolerated class of drugs. The potential to reduce cardiovascular morbidity and mortality is very high, with the potential for additional event reduction by combining substantial triglyceride lowering with the established benefits of LDL-C reduction with a single therapy. I'm very excited that this could help us with the problems that we have with getting adherence for the long term in these patients that have very high numbers of cardiovascular events. What are the take-home points here? Elevation of LDL-C and triglycerides affect about one in 10 U.S. adults at a population level and are responsible for 10%-40% of coronary and MI cohorts. It clearly is one of the drivers of residual ASCVD risk, with triglyceride-rich remnants adding to the problems of LDL cholesterol by making LDL cholesterol more atherogenic. They also have a high pancreatitis risk because of the triglyceride component. I didn't talk about this, but the big problem we face in clinical practice is drugs like omega-3 fatty acids and fibrates, they just don't lower triglycerides enough to make a difference. We can engage in polypharmacy. We can add these relatively ineffective agents to LDL-C lowering. I'm really excited about the possibility of targeting both lipid abnormalities with a single therapy given infrequently with enhanced adherence. Thank you for your attention. Thank you. We will now move on. There we go. Sorry. Here's the key takeaways from today. We've talked about a few different programs within our cardiometabolic pipeline. What ties them all together is that they all are acting on that TG-LDL spectrum of lipid disorders. Importantly, we're also building a commercial franchise to support these complementary assets because they will all have similar call points. From a business perspective, it makes a lot of sense for us to continue to develop these internally and independently. We also have the potential for multiple launches over the coming years, both independent launches and with partners. We want to continue building on the momentum that we've developed with our REDEMPLO launch in FCS, and soon potentially address high prevalence diseases such as the sHTG population, as we've heard, and as Steve has mentioned, the enormous unmet need in mixed hyperlipidemia. Zodasiran, as Jen mentioned, targets a genetically validated ANGPTL3 pathway, and still an undertreated and under-addressed population with a very severe form of hypercholesterolemia. Lastly, the promising dual functional siRNA or our dimer technology has the potential to address an extremely large mixed hyperlipidemia population, which even after a lot of innovation in the field with statins getting better and PCSK9 inhibitors, there's still a dramatic residual risk of cardiovascular disease that's just not addressed today. Importantly, we as a company have several key potential catalysts that'll give us a guidepost about where we are with these programs. SHASTA-3 and SHASTA-4 will have a top-line release in Q3 2026, which is a really important event for the company, because if successful, it enables a potential sNDA by the end of this year, then a launch in sHTG next year. YOSEMITE, the phase III program for zodasiran, should have full enrollment shortly, which also enables completion by middle of next year, then another NDA, which could enable another independent launch for us as a company. Lastly, ARO-DIMER-PA, the dual functional siRNA, will have our first human data in Q3 this year. I think that's something that we are extremely excited about, and Steve and other advisors to Arrowhead are really excited about, that I think that is underappreciated from a corporate perspective and from an investor perspective. That's something that we are going to focus on a lot over the coming years. Thank you all for joining us today. We're going to open up the call for some questions, I will take a few moments of silence just while we compile the questions. Give us a few minutes. Okay. First question comes from Joe Thome at TD Cowen, and this is for Dr. Nissen. He's asking, if plozasiran demonstrates comparable levels of acute pancreatitis risk reduction, how would you or your clinic use plozasiran versus olezarsen for sHTG, and why? Well, it's a no-brainer, really. You've got a drug that the ASO class has more AEs, shorter duration of action. Maybe even a little bit less efficacy. The small interfering RNA class can be given less frequently, which is very good for patients, is extremely well-tolerated. For me, I don't think there's really any question that really the siRNA target is going to replace antisense oligonucleotides over the next several years because of the greater efficacy, tolerability, and duration of action. Thank you. Next question is from Adam at B. Riley Securities, this is likely for the whole panel. Let me alternate to James first, then Jen and Dr. Nissen can chime in. Where is the boundary between DIMER, mixed hyperlipidemia population, and REDEMPLO's sHTG as both expand, is there a TG level where they compete for the same patient? Hey, you want me to take a first shot at that one, Vince? Yeah, take a first shot at that, James. I think it's really one we're treating as a pancreatitis drug in plozasiran, and the other is an ASCVD drug. It's, I think from my perspective, defined based on the clinical presentation or the clinical problem that the patient is having. I don't know, Jen or Steve, any other thoughts on that? Well, let me jump in and say that really are quite different populations. LDL cholesterol is a key driver of ASCVD, and lowering it is very effective. Our hope would be that if we can also reduce these triglyceride-rich lipoprotein remnants, we will get all of the benefits of LDL-C reduction that we see with PCSK9 inhibitors, plus something more. That's the population there. The DIMER is not really intended for treating hypertriglyceridemia as an isolated disorder. It's for treating both disorders simultaneously and as a means to reduce ASCVD risk. Maybe I'll just follow and say that I believe that our understanding of where the exact risk threshold starts for acute pancreatitis is really beginning to emerge. Previously, we just haven't had effective agents to even really understand what level of reduction would be necessary to reduce risk prior to the advent of the APOC3 inhibitors. Drawing these kind of false dichotomies between below or above 500, below or above 880, I think that loses a lot of the nuance. We really need to see what the final data look like from SHASTA-3 and SHASTA-4, as well as our forthcoming data from the early cohorts of the DIMER program to better understand that. Thank you. Next question from Prakhar Agrawal at Cantor, and this is probably a James question. Can you remind us of the trial powering for AP events? Yep, that's it. I'm assuming that's referring to the SHASTA- Yep. ....studies. Yeah, we will look at those as pooled studies. In a meta-analysis, we'll pool both the SHASTA-3 and the SHASTA-4 studies. We took a look at this. The study is powered based on its primary endpoint, which is reductions in triglycerides. It wasn't a priori powered around acute pancreatitis, but we took a look based on the CORE and the CORE2 data, assuming a similar effect size and a similar rate of events in the placebo arm. We'd need to have about nine events in the pooled studies to have around 80% power to detect a treatment difference. Then if you can get up into the teams, you're getting up to 90% power. Thank you. Next question from Ted Tenthoff at Piper Sandler. This is kind of along the same lines. Can you talk through the changes to the adjudication process that we made for the SHASTA-3 and SHASTA-4 studies? Sure. Yeah, I can take that one as well. In the PALISADE study, that was our FCS study, we used the strict Atlanta criteria to adjudicate AP events. Initially, we started the SHASTA-3 and SHASTA-4 studies using that strict Atlanta criteria, we pivoted to the modified Atlanta criteria, which is similar to what was used. It is actually identical to what was used in the CORE and CORE2 studies, and that allows for adjudication of events to be definitive pancreatitis, possible or probable pancreatitis. We did not have any events that required re-adjudication, no events had occurred prior to us switching over to that modified criteria. One of the things that this allows us to do is to have more events. We think that the transition made sense. The other thing we did around the same time when we made that transition was in SHASTA-3 and SHASTA-4, we switched from having patients that had a positively adjudicated event. Previously, they would roll over into an open label extension study. We changed that to such that the patients that had positively adjudicated events did not roll over. They stayed on study and stayed blinded. That allowed for some patients to have more than one event while on study, and at the end of the study, they can go into the extension program. Thank you. A question from Madison El-Saadi at B. Riley, this is likely for Dr. Nissen. This is on the dimer. Is the logic to combine two mechanisms that hit the same disease from different angles, for ASCVD, or is it to combine two targets in the same pathway for deeper single axis knockdown? Yeah. I'm not sure I actually understand the question there. Let me just think out loud about where I'm at here. We already know that lowering LDL cholesterol with a PCSK9 inhibitor does reduce cardiovascular events. We also know that many of these patients have severe hypertriglyceridemia, or at least elevated triglycerides. The concept here is that where is the residual risk coming from in the patients that have their LDLs controlled? It seems very likely, based upon the epidemiology and everything that we know, that it is the triglyceride-rich lipoproteins. Think of this as a PCSK9 inhibitor plus, and the plus is a big plus because it involves the ability to treat the triglyceride component in ASCVD risk at the same time with a single therapy for enhanced compliance, and to do so durably with relatively infrequent injections. The big problem we have is, yes, we can lower LDL cholesterol with statins, but adherence is not great. In fact, we've had lots and lots of difficulty on a societal level in getting people to the LDL levels we've targeted in our guidelines. If we can have something that can treat both components, the ability to have an added reduction in morbidity and mortality is, I think, very high, and it will certainly reduce morbidity and mortality just from the PCSK9 component alone. We think we're going to get a lot more here. Thank you. This is actually a follow-up to that last point. This is Eric Joseph from Citi. He is asking, in a registrational trial, this is more of a clinical trial design question. In a registrational trial, would you argue for an anti-PCSK9 active comparator? Wow, that's an interesting and difficult question. That would be very difficult for one very simple reason, that the sample size would likely be very large. It's hard to imagine that that would be the proper design. The right design here would be to, say, study it against usual care. Let people do whatever they want in usual care. Some of them are going to get PCSK9 inhibitors for sure, but not all of them. Some of them will get statins, some will get ezetimibe, but we'll get lower LDL cholesterols, and we'll get a lot lower triglyceride levels in the active group than we will in the usual care group. We would counsel people for usual care to follow the guidelines. Great. Thank you. That's the last question we have. I want to thank the panel, James and Steve and Jen. Thanks, everybody, for joining us today. Again, we'll be in touch on part two and part three of this summer series later in the summer. Thanks so much. Thanks, everyone