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

Good morning, everyone, and welcome to Part-1 of Arrowhead Pharmaceuticals 2026 Summer Series of R&D webinars. [Operator Instructions]. As a reminder, this call is being recorded, and a replay will be made available on the Arrowhead website following the conclusion of the event. I'd now like to turn the call over to Vince Anzalone, Vice President of Finance and Investor Relations at Arrowhead Pharmaceuticals. Please go ahead Vince.

Thank you, Tera, and thanks, everyone, for joining us today. So 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 the -- our obesity programs and also our new CNS programs, including our Tau program targeting Alzheimer's. So before we start, I 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. So 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, and then Dr. Steven 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. So 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. He has -- 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 is directed pretty much most, if not all, of the large cardiovascular [indiscernible] studies over the last couple of decades, and this is not an overstatement that I think he is insight personified when you're talking about cardiovascular disease. So thank you, Dr. Nissen for joining us today. Okay. Quick overview about Arrowhead. So 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. And importantly, we see the potential for multiple independent and partner launches over the coming years. Our pipeline already today is extremely broad. We have 20-plus clinical stage programs. Most of those are wholly owned. We also have a good mix of early, mid as well as late-stage program. So it's a very diverse pipeline. We also don't -- 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 2 to 3 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. And importantly, we think Arrowhead is the clear leader in the field of bringing RNAi therapeutics to diseases outside the liver. And as James will talk about, we can now access 7 different cell types in the body with our technology. And lastly, we had an extremely strong balance sheet, and we are funded now into potentially multiple commercial launches, again, both independently and with partners, and 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. So we are in a very solid and stable position as a company. Okay. So here is a diagram that talks about where we are looking to play with our cardiometabolic pipeline. And so if you think about this diagram on the left side, it represents elevated LDL cholesterol. And the further left you go, the more severely elevated that is. On the right side, it's elevated TGs or triglycerides. And again, the further to the right you go, more severely elevated they are. For the right side of this diagram, is FCS. So patients with TGs that are in the thousands that are at very high risk of acute pancreatitis. And 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. So patients with TGs above 500 that are at heightened risk of acute pancreatitis. And 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 [indiscernible] lipoproteins, remnant cholesterol, LDL and TGs. And for that middle part of the population or mixed hyperlipidemia, we have the ARO-DIMER-PA, the PCSK9, APOC3 DIMER. And so we're trying to kind of play in all different parts of this LDL TG spectrum. So here's a diagram of what we hope is -- will happen in the future. And obviously, this is forward-looking. We have our first launched product in REDEMPLO. On the bottom left, where it was approved for -- 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 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. And then beyond that, we have the ASCVD programs and the obesity programs, which we'll talk about later. And then down 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(a) or Lipoprotein-A. Okay. So let me turn it back over to James, and he'll talk about Arrowhead's technology and R&D process.

All right. Thanks, Vince. And just to reiterate, for those who are new to the story, Arrowhead is an siRNA company, and we don't do anything else. Everything is focused on developing siRNA drug molecules. All of our drugs are derived from a platform we call TRIM or targeted RNAi molecule. And so 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. So our goal is to maximize on-target potency while reducing or totally eliminating any risk of off-target gene silence. 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 the 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. Now Arrowhead is 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 [indiscernible] 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. And 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 the 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 0 drugs in the clinic. So we've been averaging a little better than 2 INDs or CTAs for new molecular entities per year over the last 10 years. And 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 program for the year, which leads to about 4 new clinical lead nominations annually. And naturally, there's some attrition, but we aim for an average -- an average 2 to 3 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 and target ID qualification and assessment. And 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 this 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 to 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 a serum triglyceride level of greater than 500 milligrams per deciliter affects approximately 1 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 pancreatis. Much like atherosclerosis, risk in these patients with severe hypertriglyceridemia is driven primarily by both higher levels of [indiscernible] lipoprotein. In this case, triglycerides and a history of prior clinical events, in this case, acute pancreatitis, for these reasons, patients with the highest triglycerides and prior acute pancreatitis events are often referred to as high risk severe hypertriglyceridemia, and this subset [ to ] represent about 1 in 1 million people in the United States. Of course, at the very top of this spectrum is -- or the 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 [indiscernible] recessive pathogenic variants or through established clinical criteria. And this condition affects potentially 6,500 to over 10,000 people. It's characterized by triglycerides persistently in the chylomicronemiac range, which is usually described as greater than 880 milligrams per deciliter or 10 millimoles, and 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 a 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 derepression 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 IIb trials, SHASTA-2 and MIR, establish 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 2-year open-label extension of SHASTA-2 and [ MIR ] evaluating the long-term efficacy, safety and tolerability of Plozasiran 25 milligrams dosed quarterly across the mild-severe hypertriglyceridemic populations. A total of 418 patients were enrolled in this 2-year open-label extension with approximately 250 and 170 patients from the MiR 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 milligrams quarterly was selected over the remaining 2-year follow-up period. The primary objective of the study was to assess safety though our secondary end points, including change in fasting triglycerides, APOC3 levels, non-HDL-C 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 based on median triglycerides, we're between 680 to 730 milligrams per deciliter and roughly 1 in 5 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 2-years of follow-up in the open-label extension. During the open-label extension, median triglycerides continue 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, respective. In terms of the clinical meaning of these effects, the SHASTA-2 subset in the SHASTA-2 subset about 94% of patients achieved fasting triglycerides less than 500 milligrams per deciliter, which is the well-established risk threshold for increased risk of acute pancreatitis, and about 63% achieved fasting triglycerides less than 150 milligrams 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 MIRROR subset, Plozasiran treatment was associated with median reductions in triglycerides [indiscernible] to baseline of 67% at both month 12 and months 24 and mean triglyceride productions of 62% and 63% at month 12 and 24 of the open-label extension. Consistent with these robust and sustained triglyceride reactions, 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, 3 episodes of acute pancreatitis occurred during the randomized period in 261 patients in the placebo group and 1 episode in 165 patients receiving Plozasiran 50 milligrams, 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 [indiscernible]. In the open-label extension, however, overall, 11 events were sent for adjudication by our abdominal events adjudication committee, and of these, 0 were positively adjudicated for acute pancreatitis referencing the Atlantic criteria. The extrapolated curve represented above by the dotted line shows the expected results if participants who had been initially signed 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 MIRROR studies, long-term treatment with 25 milligrams 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 2 years, this provides critical insight 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 them all, with 96% of severe hypertriglyceridemia patients received achieving triglycerides less than 500 milligrams 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 of 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 2 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 milligrams per deciliter and meeting other key eligibility described -- eligibility criteria described here were randomized to Plozasiran 25 milligrams dosed quarterly for 1-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 1 to month 12 and frequency and severity of adverse events and serious adverse events over time through month 12. The 2 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 studies was in the early 50s, 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 1/4 were enrolled in Asia or elsewhere. The enrolled population did indeed have the affected features of metabolic syndrome with a mean BMI around 31, 62% having diabetes at baseline and about 2/3 is also having hypertension at baseline. Given the high burden of the co-morbid conditions, it's not surprising to see that, that translated into considerable polypharmacy with almost [indiscernible] reporting taking at least 2 medications 69% being on statins, about 61% on fibrates, but we acknowledge the limitations of those agents in this disease state earlier. And also consistent with our understanding of this disease, there was quite a bit of variability in TG level or triglyceride levels at baseline with mean triglycerides a 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 1 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 time line should support presentation at a medical congress and publication of the results in the second half of this year; and finally, a supplemental NDA filing by the end of 2026. Turning now to another cornerstone of our late-stage Cardiometabolic pipeline. I'm also pleased to provide some updates on our Zodasiran development program. To understand Zodasiran 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 cholesterol in the range of 400 to 1,000 milligrams per deciliter. That's about 10x 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 1 in 300,000 people worldwide. And although the armamentarium of safe effective therapeutics for HOFH continues to grow, fortunately, 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 [indiscernible] 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 3, sometimes 6 lipid-lowering therapies concomitantly and specialty clinics around the U.S., just 1/4 and 32% of adults and children reach their LDL-C goals. And shockingly, despite their well-recognized atherosclerosis and ASCVD risk profile, over half of the patients in the HOFH registry or 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 HIC 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 or availability and access to safe and effect therapies for HoFH but also for treatment regimens to which patients can readily adhere given the considerable polypharmacy. Therapies targeting angiopoietin-like-3 the or ANGPTL3, thankfully offering new promise for HoFH patients. ANGPTL3 is a hepatocyte-expressed regulator of lipid and lipoprotein metabolism with multiple potential modes of action depicted in the schematic care, 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 ANGPTL-3 loss-of-function genetic variance lead to enhanced LPL and EL activity, thereby resulting in substantial lifelong decreases in circulating LDL-C and other [ athrogenic ] lipoproteins driving a decreased lifetime risk of ASCVD. Importantly, there is no known adverse phenotype associated with this genetic deficiency and the mechanism of ANGPTL3 is independent of the LDL receptor pathway. And 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 derepression of both LPL and endothelial lipase. In this development program, we have 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 population studied. Zodasiran across these studies has shown a reassuring safety profile with no changes in platelets nonprogressive signals of worsening hypoglycemia and no severe signals of hot or renal toxicity thus far. Gateway was an open-label remised Phase II study designed to evaluate efficacy and safety of zodasiran, our liver-targeted RNAi therapeutic in patients with HoFH. The study was conducted at 7 clinical sites across the world and patients aged 16 years or older with documented HoFH who are receiving stated lipid lowering therapy and were on stable diet at baseline, who had a screening LDL-cholesterol greater than 100 mgs per deciliter and triglycerides less than 300 mg per deciliter were randomized in one-to-one fashion to receive Zodasiran 200 milligrams or 300 milligrams on day 1 and month 3. 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 with the lowering therapy. At month-6, patients showed substantial dose-responsive reductions in fasting LDL-C with means of about negative 36% and negative 40% in the 200- and 300-milligram dose groups respective. And this was consistent with what we had previously reported in interim results. Following partial washout, all patients opened -- 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. And the overall safety and tolerability of Zodasiran was quite reassuring and consistent with what had been previously noted in other studies. These promising results inform 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, and 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 2:1 to Zodasiran 200-milligram dose at day 1 and then quarterly after a loading dose at month 1 versus placebo to match, and 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 by incident sincerity of treatment-emergent adverse events. The study is nearing completion, at a total of 47 sites across 21 countries worldwide. And ultimately, we are targeting enrollment of 60 patients worldwide. YOSEMITE complete enrollment. We are simultaneously pleased to report the launch of a broader pediatric program in AFH, 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 [indiscernible] this first patient later this summer. We believe that successful execution of this study could then pave the way for subsequent pivotal studies, younger age groups. So to recap, while we eagerly await top line data from SHASTA-3 and 4 programs of Plozasiran severe hypertriglyceridemia, we continue to make strides in our VISTA development program of Zodasiran-HOFH. YOSEMITE is expected to complete enrollment any day now and completion of 12-month double-blind -- completion of the 12-month double-blind portion of the study would be expected in summer 2027, which would help to support our first new drug application for Zodasiran in the second half of 2027. And now I'm pleased to hand it back to Dr. Hamilton to discuss ARO-DIMER-PA.

Thanks, Jen. So another area of successful innovation at Arrowhead has been in the development of siRNA DIMER or dual function technology. This involves the linkage of 2 siRNA sequences, each against a different gene target, allowing the targeted silencing of 2 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 2 targets that made sense medically to combine and that we're well validated, and we think that combining siRNA is targeted PCSK9 and APOC3 make a lot of sense as an approach to potentially treat patients with mixed hyperlipidemia, 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 [indiscernible] B 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 dis-lipidemic 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 to 499 milligrams per deciliter as well as either non-HDL greater than 100 or LDL greater than 70 milligrams per deciliter at baseline. In terms of progress, we should have single escalating dose cohorts fully enrolled by mid [indiscernible] summer and full study enrollment completed by the end of the third quarter, and we still anticipate sharing some top line data sometime in third quarter. I'll now turn things over to Dr. Steven Nissen from the Cleveland Clinic, who will provide more details on the mixed hyperlipidemia patient population. Steve?

Thank you very much, James. And I really appreciate the opportunity to join you on discuss this, I think innovative approach to targeting 2 lipid abnormalities with a single molecule. So let me talk about mixed hyperlipidemia. But first, let me introduce myself. I'm the Chief Academic Officer of the Heart, Vascular and Thoracic Institute at Cleveland Clinic and Preventive Cardiologists. I've been involved in clinical trials for a number of years. What is a mixed hyperlipidemia. Well, it's really pretty simple. It's a simultaneous elevation of LDL cholesterol and triglycerides, often accompanied by reduced HDL cholestrol. It's distinct from isolated hypercholesterolemia or isolated hypertriglyceridemia because it requires both. And importantly, the clinical hallmark is an increased number of circulating Apo-B containing particles -- the atherogenic particles, but they 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 and quite a substantial overlap group that have both abnormalities in daily practice. Now we talk about the atherogenic lipid triad, and that's triglyceride-rich elements, 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 common drivers, including insulin resistance metabolic syndrome, hepatic VLDL over production, but very importantly, highlighted here is impaired lipoprotein lipase clearance. As you've heard from Jen Hellawell, is something being targeted by Plozasiran and Zodasiran. And that leads to the atherogenic lipid triad. Now how common is this? Well, if you take hypercholesterolemia, total cholesterol greater than 240 and 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. So there was a study done by [indiscernible]. This is a very large study being done by the Federal Government in patients with lipid disorders. And what you see is that it's common amongst all groups, but highest in Mexican-Americans, a little bit less likely in blacks. And you can see in gold, hypercholesterolemia and in blue hypertriglyceridemia and their frequencies of distribution in the [ N-HANES ] cohort. Now 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% to 0.4% of the population. So genetically driven, not driven by presence of either diabetes or obesity or any other drivers. But even though it's only 0.3% to 0.4% of the population, that's about 1.3 million people that have this disorder, and you will see clusters and families of this syndrome. But 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. So it really does lead to a lot of cardiovascular morbidity and mortality. Now how do you 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. It's come from a very large study done in statin-treated patients. And in these patients, really LDL control is not sufficient. And here's why. Even with intensive statin therapy the 5-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, a low AGL that statins do not fully address. And of course, as you've heard from others on this call today, there is a pancreatitis risk, for triglycerides above 500, approximately 1% risk and at 1000 a 5% risk and at 1,771 a 16% risk. And I do see these patients referred to us, they are really quite needy patients who have had, in many cases, episodes for acute pancreatitis, sometimes more than a dozen episodes over a long period of time. Now we have great treatments for LDL cholesterol, but we're not getting there. And unfortunately, there's a shocking side, but in people with an LDL cholesterol greater than 190 milligrams per deciliter, at least 1/4 of them in recent periods of time are both untreated and unaware. And 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. So 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 so that we clearly have 2 targets that we have an approach for treatment. We are hoping to be able to simultaneous and durable reductions in LDL cholesterol in the range of 50% and triglycerides in the range of 70% or even bigger with this DIMER with this dual-targeted siRNA with relatively infrequent injections, perhaps 4 times a year. That enhances adherence. Adherence is an enormous problem in treating these patients. And the good news is the 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. So 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. And 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. So what are the take-home points here? Elevation of LDL-C and triglycerides affect about 1 in 10 U.S. adults at a population level and are responsible for 10% to 40% of coronary and MI cohorts. It clearly is one of the drivers of residual ASCVD risk triglyceride-rich remnants adding to the problem of LDL-cholesterol by making LDL cholesterol more atherogenic. They also have a high pancreatitis risk because of the triglyceride component. And 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 triglyceride enough to make a difference. And so we can engage in polypharmacy. We can add these relatively ineffective agents to LDL-C lowering, but 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. So we will now move on -- there we go. Okay. So here's the key takeaways from today. So 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 most -- they will all have similar call points. So 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 under-treated and under-addressed population with a very severe form of hypercholesterolemia. Lastly, the promising dual functional siRNA or 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. And importantly, we, as a company, have several key potential catalysts that will kind of give us a guidepost about where we are with these programs. SHASTA-3 and 4 we'll have the top line release in Q3 of 2026, which is a really important event for the company because if successful, it enables a potential sNDA by the end of this year and 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 and then another NDA, which could enable another independent launch for us as a company. And again, lastly, ARO-DIMER-PA, the dual functional siRNA we'll have our first human data in Q3 of this year. And I think that that's something that we are extremely excited about. And Steve and other advisers to Arrowhead are really excited about. I think that is underappreciated from a corporate perspective and from an investor perspective. So that's something that we are going to focus on a lot over the coming years. So thank you all for joining us today. We're going to open up the call for some questions. And I will take a few moments of silence just while we compile the questions. So give us a few minutes.

Okay. First question comes from Joe Thome at TD Cowen, and this is for Dr. Nissen and he's asking if Plozasiran demonstrated comparable levels of acute pancreatitis risk reduction, how would you or your clinic use Plozasiran versus [indiscernible] for SHTG and why?

Well, it is 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, a small interfering RNA class can be given less frequently, which is very good for patients, is extremely well tolerated. And so for me, I don't think there's really any question that really, the siRNA target is going to replace [ anti-sensonucleotides ] over the next several years. because of the greater efficacy, tolerability and duration of action.

Next question is [indiscernible] from B. Riley Securities, and this is likely for the whole panel. So let me, I'll turn it to James first and then Jen and Dr. Nissen can chime in. Where is the boundary between dimer mixed hyperlipidemia population and REDEMPLO SHTG has both expand and is there a TG level where they compete for the same patient?

Do you want me to take a first shot at that one, Vince?

Yes, 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. So 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?

Let me jump in and say that really, it's really are quite different populations. LDL cholesterol is a key driver of ASCVD and lowering it is very effective. And 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. So that's the population there. But 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 understand what level of reduction would be necessary to reduce risk prior to the advent of the APOC3 inhibitor. So drawing these kind of false [indiscernible] between below or above 500, below or above 880, I think that loses a lot of the nuance, and we really need to see what the final data look like from SHASTA-3 and 4 as well as our forthcoming data from the early cohorts of the DIMER program to better understand that.

Next question from Prakar Agarwal at Cantor, and this is probably a, James question. Can you remind us of the trial powering AP events? Yes. That's it.

I'm assuming that's referring to the SHASTA study. Yes. So we will look at those as pooled studies. We'll pool in a meta-analysis will pool both the SHASTA-3 and the SHASTA-4 studies. And we took a look at this. And the study is powered based on its primary endpoint, which is reductions in triglycerides. It wasn't a priority powered around acute pancreatitis. But we took a look based on the CORE and the CORE II data, assuming a similar effect size and a similar rate of events in the placebo arm. We need to have about 9 events in the pooled studies to have around 80% power to detect a treatment difference. And then if you can get up into the teams you're getting up to 90% power.

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 4 studies?

Sure. Yes, I can take that one as well. in the PALISADE study, so that was our FCS study. We used the strict Atlanta criteria to adjudicate AP events. We switched -- initially, we started the SHASTA-3 and 4 studies using that strict Atlantic criteria, but we pivoted to the modified Atlanta criteria, which is similar to what was used. It's actually identical to what was used in the CORE and CORE-2 studies, and that allows for adjudication of events to be definitive pancreatitis, possible or probable pancreatitis. We didn't have any events that required re-adjudication. So no events had occurred prior to us switching over to that modified criteria. And one of the things that this allows us to do is to have more events. So we think that the transition made sense. The other thing we did around the same time when we made that transition was in SHASTA-4 and 4, we switched from having patients that had a positively adjudicated event. Previously, they would roll over into an openable extension study. We changed that to such that the patients that had possibly adjudicated events did not roll over. They stayed on study and stay blinded. So that allowed for some patients to have more than one events while on study. And at the end of the study, they can go into the extension program.

And a question from Madison El-Saadi at B. Riley, and this is likely for Dr. Nissen. This is on the DIMER. Is the logic to combine 2 mechanisms that hit the same disease from different angles for ASCVD or is it to combine 2 targets in the same pathway for deeper single access knockdown?

Yes, 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. But we also know that many of these patients have severe Hypertriglyceridemia or at least elevated doses. And the concept here is that where is the residual risk coming in the patients that have their LDLs controlled. And it seems very likely based upon the epidemiology and everything that we know that it is the triglyceride-rich lipoproteins. And so 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. And 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. But if you -- if we can have something that can treat both components, the ability to have an added reduction in morbidity, mortality is, I think, very high and it will certainly reduce morbidity and mortality just from the PCSK9 component alone, but we think we're going to get a lot more here.

And this is actually a follow-up to that last point. This is Eric Joseph from Citi. He is asking would you -- in a registrational trial, this is more of a 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. And 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 getting PCSK9 for sure, but not all of them. And some of that will get statin, someone will get [indiscernible], 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. And we would [indiscernible] people for usual care to file the guidelines.

Great. Thank you. And that's the last question we have. So I want to thank the panel, James and Steve and Jen, and thanks, everybody, for joining us today. And again, we'll be in touch on Part 2 and Part 3 of this summer series later in the summer. Thanks so much.