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European Society of Cardiology Congress 2026 Investor Webcast August 31, 2026 For investor communication only. Not for use in product promotion
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Welcome and Introductions Vince Anzalone, CFA Senior Vice President, Investor Relations European Society of Cardiology Congress 2026
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3 Safe Harbor Statement For investor communication only. Not for use in product promotion This presentation contains forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995. These statements are based upon our current expectations and speak only as of the date hereof. Our actual results may differ materially and adversely from those expressed in any forward-looking statements as a result of various factors and uncertainties, including, without limitation, our developmental stage and limited operating history, our ability to successfully and timely develop products, entering into new collaborations and achieving existing projected milestones, rapid technological changes in our markets, demand for our future products, legislative, regulatory and competitive developments and general economic conditions. Our Annual Report on Form 10-K, recent and forthcoming Quarterly Reports on Form 10-Q, recent Current Reports on Forms 8-K, and other SEC filings discuss some of the important risk factors that may affect our ability to achieve the anticipated results, as well as our business, results of operations and financial condition. Readers are cautioned not to place undue reliance on these forward- looking statements. Additionally, Arrowhead disclaims any intent to update these forward- looking statements to reflect subsequent developments.
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4 Key Opinion Leader Gerald F Watts, MD University of Western Australia, Perth Gerald Watts trained at Imperial & King’s College, London University, and was a scholar at Wolfson College, Oxford University. He is a senior consultant physician, specializing in the rapidly developing field of cardiometabolic medicine, and current chair of the Familial Hypercholesterolemia Australasia Network. He leads the Cardio-metabolic Service in the Departments of Cardiology and Internal Medicine at Royal Perth Hospital and is Winthrop Professor of Cardio-metabolic Medicine in the University of Western Australia. Research interests include fundamental and applied aspects of lipid disorders and cardiovascular prevention, and improving healthcare delivery for patients with high-risk dyslipidemias, in particular familial hypercholesterolemia and hyperchylomicronemia. For investor communication only. Not for use in product promotion
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5 Key Opinion Leader Børge Nordestgaard, MD Copenhagen University Hospital, Copenhagen Børge Nordestgaard is Professor and Chief Physician at Herlev og Gentofte Hospital, Copenhagen University Hospital, University of Copenhagen. Prof. Nordestgaard has studied and worked in Copenhagen, New York, and London. He has for more than 30 years continued his interest in the pathogenesis, diagnosis and treatment of familial hypercholesterolemia, hyperlipidemia, atherosclerosis and cardiovascular disease, and has written extensively on these conditions. He is chairing the Copenhagen General Population Study and is also a steering committee member of the Copenhagen City Heart Study and of several randomised intervention trials. For investor communication only. Not for use in product promotion
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6 Agenda For investor communication only. Not for use in product promotion Topic Presenter Introduction Vince Anzalone, CFA Overview of Severe Hypertriglyceridemia Jennifer Hellawell, MD SHASTA-3 and SHASTA-4 Full Results Gerald Watts, MD University of Western Australia SHASTA-3 and SHASTA-4 Discussion Børge Nordestgaard, MD Copenhagen University Hospital Commercialization Efforts Andy Davis, MBA Key Takeaways Vince Anzalone, CFA Q&A Panel
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7 Bringing RNA Interference to Patients For investor communication only. Not for use in product promotion Financial Resources • Strong balance sheet with funding to multiple potential commercial launches • Additional non-dilutive capital expected from Madrigal, Sarepta, Amgen, Takeda, GSK, Novartis, and Royalty Pharma as milestones and royalties are earned Proprietary Platform • Targeted RNAi Molecules platform (TRiM ) designed for deep and durable gene silencing • Fulfilling the promise of bringing RNAi therapeutics to diseases outside of the liver • Potential to be best-in-class across several tissue types Arrowhead Pharmaceuticals is a RNAi therapeutics platform company with a broad pipeline of wholly owned and partnered candidates and achieved its first commercial launch in 2025 Broad Pipeline • 20+ clinical stage programs with majority wholly owned • Mix of early, mid, and late-stage candidates targeting rare and high prevalence diseases • Growing pipeline with 2-3 new clinical programs planned per year First Commercial Launch in 2025 • REDEMPLO® approved in US, European Union, Canada, Australia, and China to reduce triglycerides in adults with familial chylomicronemia syndrome (FCS) • Potential Multi-billion-dollar opportunity across future indications • Potential for additional independent and partner launches in coming years
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8 TRiM Platform Enables Delivery to Seven Cell Types For investor communication only. Not for use in product promotion Liver Lung Skeletal Muscle CNS Adipose Ocular Cardio- myocyte Strong clinical validation Deep lung clinical validation (RAGE) Early clinical stage Early clinical stage Early clinical validation Preclinical Stage Preclinical Stage Arrowhead is Fulfilling the Promise of Bringing RNAi Throughout the Body
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9 Robust Pipeline with Long-term Growth Opportunities For investor communication only. Not for use in product promotion
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10 Plozasiran Paradigm Shifting SHASTA-3 and SHASTA-4 Results For investor communication only. Not for use in product promotion Triglyceride (TG) reductions of ~80% across the sHTG spectrum, with more than 90% achieving TG levels below risk thresholds for acute pancreatitis (AP) Cumulative AP events reduced by 78% with a 100% reduction in the highest-risk subgroup, patients with TG above 880 mg/dL and a prior history of AP Favorable safety and tolerability profile, with overall treatment-emergent adverse events similar between plozasiran and placebo groups Accepted in Major Medical Journal, more details to follow
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Overview of Severe Hypertriglyceridemia Jennifer Hellawell, MD, FACC Vice President, Clinical Development European Society of Cardiology Congress 2026
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12 sHTG Represents a Spectrum of Elevated Triglycerides For investor communication only. Not for use in product promotion Source: Nemeth, Journal of Clinical Medicine 2022; Rabacchi, Atherosclerosis 2015; Company Estimates High-Risk SHTG Severe Hypertriglyceridemia (SHTG) SHTG • TGs ≥ 500 mg/dL • >3+ million people • Elevated Risk of AP High-Risk SHTG • TGs ≥ 880 mg/dL or ≥ 500 mg/dL With Prior AP History • ~1 million people • Higher Risk of AP FCS (Genetic or Clinical) • Persistently Elevated TGs ≥ 880 mg/dL • Prevalent Prior History of AP • Potentially 6500+ people • Extremely High Risk of AP FCS (Genetic or Clinical) Figure Not to Scale
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13 sHTG is a Common & Grievous Disease with High Unmet Need For investor communication only. Not for use in product promotion Source: Mach F, et al. Eur Heart J. 2025 Nov 7;46(42):4359-4378. Kessler AS, et al. J Clin Lipidol. 2025 Jul-Aug;19(4):931-941. Residual Atherosclerotic Risk Acute and chronic pancreatitis ~ 1 : 100 Prevalence sHTG is a Common and Grievous Disease • The patient journey usually evolves from hidden genetic and/or metabolic risk factors to sudden acute crises prompting ER visits • Attacks of acute pancreatitis (AP) can bring excruciating abdominal pain, nausea, vomiting, inability to eat and ICU stays • After stabilization, these acute crises are followed by intensive chronic lifestyle and medical adjustments, but many patients get lost in transitions of care to the outpatient setting sHTG Patients at Risk Despite Available Therapies • Extreme lifestyle modifications (cessation of alcohol consumption, reduced fat and carbohydrates) weight loss, and blood sugar control are the most effective ways to lower TG levels • Adhering to these regimens is challenging for patients and impairs quality of life • Conventional therapies, including fibrates, omega-3 fatty acids, and statins only modestly lowers TG levels and do not lower risk of AP
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SHASTA-3 and SHASTA-4 Study Results Gerald Watts, MD University of Western Australia, Perth European Society of Cardiology Congress 2026
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Plozasiran for Severe Hypertriglyceridemia and Risk of Pancreatitis: The SHASTA-3 and SHASTA-4 Pivotal Trial 12-Month Results Gerald F . Watts, DSc, MD, PhD1; Christie M. Ballantyne, MD2; Agustin Blanco Echevarria, MD, PhD3; Jamie Smith, MD4; Robert S. Rosenson, MD5; Savitha Subramanian MD6; James Trippi, MD7; Norman Lepor, MD8; Archna Bajaj, MD9; Vladimir Blaha, MD, PhD10; Russell Scott, MD, PhD11; Alexis Baass, MD12; Ira J. Goldberg, MD13; Antonio Gallo, MD, PhD14; Jose Luis Diaz, MD, PhD15; Manish Saxena, MBBS, MSc, FESC16; Jianping Li, MD17; Ran Fu, PhD18; Lalitha Aiyer, MD, MS, MBA18; Jennifer Hellawell, MD18; James Hamilton, MD, MBA18; Daniel Gaudet, MD, PhD19 1School of Medicine, University of Western Australia, and the Department of Cardiology, Royal Perth Hospital —Perth, Australia; 2Baylor College of Medicine and the Texas Heart Institute—Houston, Texas; 3Hospital Universitario 12 de Octubre, Madrid, Spain; 4Torbay and South Devon NHS Foundation Trust - Torbay Hospital (Department of Diabetes and Endocrinology), Torquay, UK; 5Metabolism and Lipids Program, Mount Sinai Fuster Heart Hospital, Icahn School of Medicine, Mount Sinai, NY, USA; 6University of Washington, Seattle, Washington; 7Ascension St. Vincent Heart Center, Indianapolis, Indiana; 8National Heart Institute, Beverly Hills, CA, USA; 9University of Pennsylvania, Philadelphia; 10Third Department of Internal Medicine–Metabolism and Gerontology, Faculty of Medicine, Hradec Králové, University Hospital Hradec Králové and Charle s University, Czech Republic; 11New Zealand Clinical Research, Christchurch, New Zealand; 12Institute de recherches cliniques de Montréal, Canada; 13NYU Langone Health, New York, NY, USA; 14APHP Hôpital Universitaire Pitié Salpêtrière, France; 15Complejo Hospitalario Universitario de A Coruña, Galicia, Spain; 16Barts Health NHS Trust and Queen Mary University London, UK; 17Peking University First Hospital, China; 18Arrowhead Pharmaceuticals, Pasadena, CA, USA; 19Université de Montréal and ECOGENE 21, Montréal Canada Presented at the European Society of Cardiology (ESC) Congress | August 28-31, 2026 | Munich, Germany
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| 16 Background: Severe Hypertriglyceridemia (sHTG) › sHTG (triglycerides ≥5.65 mmol/L [≥500 mg/dL]) affects approximately 1% of the population and increases the risk of acute pancreatitis (AP)1,2 › sHTG is a heterogeneous disorder driven by polygenic factors and secondary causes, such as obesity and type 2 diabetes3,4 › Despite lifestyle changes and current lipid-lowering therapies, many patients do not achieve treatment goals (TGs ≤5.65 mmol/L [≤500 mg/dL]) with an elevated risk of AP5 › Apolipoprotein C-III (APOC3) is a key regulator of TG-rich lipoprotein metabolism and a validated therapeutic target3 › Plozasiran, a hepatocyte-targeted siRNA that reduces hepatic APOC3 synthesis, was evaluated in adults with sHTG in the phase 3 SHASTA-3 and SHASTA-4 trials6 1. Hansen SEJ, et al. Clin Chem 2023;69(10):1132–1144. (In eng). DOI: 10.1093/clinchem/hvad094. 2. Varbo A, Nordestgaard BG. Eur Heart J 2021;42(47):4833–4843. DOI: 10.1093/eurheartj/ehab293. 3. Packard CJ, et al. Cardiovasc Res 2024;119(18):2843–2857. (In eng). DOI: 10.1093/cvr/cvad177. 4. Filtz A, et al. Am J Prev Cardiol 2024;18:100648. DOI: https://doi.org/10.1016/j.ajpc.2024.100648. 5. Berglund L, et al. J Clin Endocrinol Metab 2012;97(9):2969–89. (In eng). DOI: 10.1210/jc.2011-3213. 6. US Food and Drug Administration. FDA Approves Drug to Reduce Triglycerides in Adults with Familial Chylomicronemia Syndrome. Available at https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-drug- reduce-triglycerides-adults-familial-chylomicronemia-syndrome. Accessed Nov 23, 2025. AP, acute pancreatitis; APOC3, apolipoprotein C3; sHTG, severe hypertriglyceridemia; TG, triglycerides.
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| 17 Background: Plozasiran is an Investigational siRNA Therapeutic Targeting APOC3, a Key Regulator of TG and TRL Metabolism TRL Chylomicron VLDL LPL Independent LPL Dependent Hepatocyte TRL-Remnants APOC3 Silencing APOC3 enhances lipolytic clearance of TRLs APOC3 inhibits lipolysis and hepatic clearance of TRLs, increasing TGs HYPERTRIGLYCERIDEMIA1,2 Silencing of APOC3 enhances lipolysis and hepatic clearance of TRLs, reducing TGs PLOZASIRAN2 APOC3 APOC3 Plozasiran TRL Chylomicron VLDL LPL Dependent LPL Independent Hepatocyte TRL-Remnants APOC3 APOC3 inhibits (1) LPL and HL, preventing lipolysis of TRLs; (2) hepatic receptor uptake of TRL-remnants APOC3, apolipoprotein C3; HL, hepatic lipase; LPL, lipoprotein lipase; siRNA, small interfering RNA; TG, triglycerides; TRL, triglyceride rich lipoproteins; VLDL, very low-density lipoprotein. 1. Van Zwol W, et al. J Clin Med. 2019; 8:1085. 2. Ballantyne CM, et al. New Engl J Med. 2024; Published online: May 28, 2024. DOI: 10.1056/NEJMoa2404143.
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| 18 Methods: Study Schema SCREENING RANDOMIZATION 2:1 SHASTA-3SHASTA-4 2:1 SCREENING RANDOMIZATION DOUBLE-BLIND* OPEN-LABEL EXTENSION† Plozasiran 25 mg Plozasiran 25 mg N 297 Placebo N 149 Plozasiran 25 mg N 207 Placebo N 104 Up to 12 Months (Q3M Dosing) Up to 24 Months Q3M Dosing ABPM, ambulatory blood pressure monitoring; MRI-PDFF, magnetic resonance imaging-proton density fat fraction; OLE, open-label extension; Q3M, every 3 months. *A subset of patients enrolled in SHASTA-3 underwent serial MRI-PDFF in a substudy to assess change in liver fat content. MRI-PDFF was conducted at screening and Month 12 at sites where MRI-PDFF testing is available. ABPM was a substudy of SHASTA-4 and was conducted for the evaluation of changes in systolic and diastolic blood pressures in a total of up to 60 patients. †All patients will have the option to participate in an open-label extension study comprised of patients from both studies. Patients who opt out of the OLE will have an additional 3-month follow-up visit at Month 15.
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| 19 SHASTA 3/4 Baseline Characteristics AP, acute pancreatitis; BMI, body mass index; HbA1c, glycosylated hemoglobin; Q1, Q3, interquartile range; SD, standard deviation; TG, triglycerides. *Data are reported as mean (±SD) unless otherwise noted. aFor fasting TG concentrations, baseline is defined as the average (i.e., geometric mean) of Day 1 pre -dose assessment, and the last fasting TG concentration collected during the screening period. bDiabetic patients are defined as having HbA1c ≥6.5% or fasting glucose 7 mmol/L (≥126 mg/dL) or with medical history of ‘diabetes’ or receiving diabetic medications at baseline. Demographics/Characteristic SHASTA-3 SHASTA-4 Placebo (n=149) Plozasiran (n=297) Placebo (n=104) Plozasiran (n=207) Age (years), mean (SD) 51 (12) 52 (12) 53 (12) 53 (11) Sex at birth, n (%), Male 122 (82) 247 (83) 69 (66) 160 (77) Race, n (%) White 109 (73) 223 (75) 87 (84) 184 (89) Asian 38 (26) 62 (21) 9 (8.7) 9 (4.3) Black or African American 0 3 (1.0) 3 (2.9) 13 (6.3) Ethnicity, Hispanic, n (%) 33 (22) 57 (19) 21 (20) 39 (19) BMI (kg/m2), mean (SD) 30 (4.8) 31 (5.3) 31 (5.4) 32 (4.9) History of cardiovascular disease, n (%) 37 (25) 104 (35) 35 (34) 68 (33) History of diabetes mellitus, n (%) 81 (54) 174 (59) 57 (55) 130 (63) History of AP, n (%) 37 (25) 57 (19) 21 (20) 45 (22) Triglycerides (mmol/L)a Mean (SD) 9.3 (5.8) 9.4 (5.7) 10.6 (7.7) 10.8 (7.4) Median (Q1, Q3) 7.6 (6.2, 11.1) 7.5 (6.1, 10.8) 8.0 (6.3, 12.2) 8.3 (6.4, 12.5) ≥ 10 mmol/L, n (%) 44 (30) 91 (31) 38 (37) 77 (37) HbA1c (%)b, mean (SD) 6.4 (1.1) 6.4 (1.1) 6.4 (1.1) 6.6 (1.2) TG-lowering therapy, n(%) Fibrates 94 (63) 185 (62) 55 (53) 127 (61) Omega-3 fatty acid 30 (20) 79 (27) 35 (34) 54 (26) Lipid-lowering therapy, n (%) Statin 95 (64) 204 (69) 78 (75) 148 (72) Ezetimibe 37 (25) 73 (25) 20 (19) 44 (21) ≥2 therapies 97 (65) 194 (65) 75 (72) 138 (67)
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| 20 Plozasiran Showed Sustained TG Reductions in SHASTA-3 and 4 SHASTA-3 Plozasiran 25 mg SHASTA-3 Placebo SHASTA-4 Plozasiran 25 mg SHASTA-4 Placebo Triglycerides Median (95% CI) % Change Over Time 0 3 6 9 12 -100 -75 -50 -25 0 25 Visit (Month) Median Percent Change (Q1, Q3) From Baseline P<0.0001 for plozasiran vs placebo for all time points BL, baseline; CI, confidence interval; Q1, Q3, interquartile range; TG, triglycerides. 10 TG Values plotted are median (95% CI). %TG (Q1, Q3): -79% (-65, -85); -81% (-68, -88) -79% P<0.0001 -81% P<0.0001 Primary Endpoint: TG % Change from BL at Month 12 Placebo Plozasiran
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| 21 Plozasiran Lowered TGs and Other Lipid Parameters Including Remnant-C and Non-HDL-C Primary Endpoint Median (Q1, Q3) Percent Change from Baseline -79 -84 -72 -28 -82 -85-81 -84 -76 -38 -84 -85 -100 -90 -80 -70 -60 -50 -40 -30 -20 -10 0 Triglycerides: Month 12 Triglycerides: Month 10 Remnant-C (VLDL-C) at Month 12 Non-HDL-C at Month 12 ApoC3 at Month 12 Triglycerides: Month 12 Patients with BL ≥10 mmol/L (≥880 mg/dL) SHASTA-3 Plozasiran 25 mg SHASTA-4 Plozasiran 25 mg P<0.001 for each dose vs placebo for all parameters % Change in TGs from BL at Month 10 and 12 and Among Patients with BL TG ≥10 mmol/L (≥880 mg/dL) at Month 12 % Change in Remnant-C (VLDL-C), Non-HDL-C, and ApoC3 from BL at Month 12 ApoC3, apolipoprotein C3; BL, baseline; non-HDL-C, non-high-density lipoprotein cholesterol; Q1, Q3, interquartile range; remnant-C, remnant cholesterol; TG, triglycerides; VLDL-C, very low-density lipoprotein cholesterol Data are shown as median. Error bars are Q1, Q3.
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| 22 Plozasiran Lowered TG Levels Below Clinically Relevant Thresholds at 12 Months Percent of Patients SHASTA-3 Plozasiran 25 mg SHASTA-3 Placebo SHASTA-4 Plozasiran 25 mg SHASTA-4 Placebo n/N’= 71/140 255/279 49/98 175/189 11/140 146/279 2/98 104/189 Odds ratio (95% CI): 8.2 (4.8, 14); P<0.0001 Odds ratio (95% CI): 9.4 (4.8, 19); P<0.0001 Odds ratio (95% CI): 12 (6.2, 23); P<0.0001 Odds ratio (95% CI): 52 (13, 216); P<0.0001 CI, confidence interval; TG, triglycerides. %=100*n/N’, where N’ is the number of patients available at the specific visit. 51 8 91 5250 2 93 55 0 20 40 60 80 100 Achieved <5.65 mmol/L (<500 mg/dL) Achieved <1.7 mmol/L (<150 mg/dL)
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| 23 Plozasiran Reduced AP Event Frequency and Time to First AP Event in the Broad sHTG Population Event Rate of All Adjudicated AP Events 253 252 251 250 250 248 246 244 239 237 234 230 62 504 503 502 502 499 497 496 493 488 485 473 468 137 Cumulative Incidence of First Adjudicated AP Event Months Months 0% 5% 10% 15% 0 1 2 3 4 5 6 7 8 9 10 11 12 0% 5% 10% 15% 0 1 2 3 4 5 6 7 8 9 10 11 12 Positively adjudicated AP events included documented, probable, and possible AP; Absolute risk reduction (ARR) is the difference in event rates between treatment and control groups. Number needed to treat (NNT) is the reciprocal of ARR and represents the number of patients who must be treated over a specified period to prevent one additional adverse event. ARR, absolute risk reduction; AP, acute pancreatitis; CI, confidence intervals; HR, hazard ratio; NNT, number needed to treat; RR, risk ratio; TG, triglycerides. Adjudicated AP Event Rate: Total AP Events Time to First AP Event 182 days 283 days Pooled placebo pooled plozasiran Median time to first adjudicated AP event RR 0.22 (95% CI: 0.07, 0.67); P = 0.008 4.1% ARR in incidence of total events 24 NNT over 1 year HR 0.26 (95% CI: 0.09, 0.78); P = 0.016 Pooled SHASTA-3/4 Plozasiran 25 mgPooled SHASTA-3/4 Placebo No. at Risk Pooled Placebo 253 252 251 250 250 248 246 244 239 237 234 230 62 Pooled Plozasiran 504 503 502 502 499 497 496 493 488 485 473 468 137
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| 24Positively adjudicated AP events included documented, probable, and possible AP. * Kaplan Meier curve not shown for this subgroup. ARR, absolute risk reduction; AP, acute pancreatitis; CI, confidence intervals; HR, hazard ratio; Hx, history; NNT, number needed to treat; RR, risk ratio; TG, triglycerides. Plozasiran Reduced Frequency of AP Events in High-Risk Subgroups (TG ≥500+Hx AP) Event Rate of Adjudicated AP Events in Hx of AP Subgroup 0% 5% 10% 15% 0 1 2 3 4 5 6 7 8 9 10 11 12 RR 0.09 (95% CI: 0.02, 0.41); P = 0.002 34% ARR in incidence of total events with history of AP 3 NNT over 1 year Months Adjudicated AP Event Rate: TG≥500 and Hx of AP Pooled SHASTA-3/4 Plozasiran 25 mg, n=60Pooled SHASTA-3/4 Placebo, n=35 In highest risk subgroup, TG ≥10 mmol/L (880 mg/dL) with a Hx of AP Plozasiran reduced AP event rate by 100%*
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| 25 Summary of Adverse Events › TEAEs leading to discontinuation remained low (1.2%) › AEs were generally similar between groups › No cases of anaphylaxis or systemic hypersensitivity › Worsening glycemic control occurred in 14% and 9% of patients in the plozasiran and placebo groups › No clinically meaningful changes in platelet counts observed › No meaningful elevations in ALT or AST relative to placebo • No cases met Hy’s law criteria › No statistically significant (p=0.70) treatment-emergent increase in HFF ALT, alanine aminotransferase; AST, aspartate aminotransferase; HFF, hepatic fat fraction; MRI-PDFF, magnetic resonance imaging-proton density fat fraction; SD, standard deviation; SAE, serious adverse event; TEAE, treatment-emergent adverse event; ULN, upper limit of normal. Liver fat using MRI-PDFF (%), mean (SD) SHASTA-3 Placebo (n=13) Plozasiran (n=23) Total (n=36) Baseline, mean (SD) 16.2 (8.3) 14.0 (8.0) 14.8 (8.1) Month 12, mean (SD) 15.6 (9.5) 15.0 (9.8) 15.2 (9.5) Change from baseline, mean (SD) -0.5 (7.3) 1.0 (8.9) 0.5 (8.3) SHASTA-3/4 Pooled Placebo (n=252) Pooled Plozasiran (n=504) Total (N=756) All TEAEs, n (%) 184 (73) 368 (73) 552 (73) Most common TEAEs ≥5% Worsening glycemic control 22 (8.7) 72 (14) 94 (12) Diarrhea 8 (3.2) 28 (5.6) 36 (4.8) Abdominal pain 17 (6.7) 13 (2.6) 30 (4.0) Serious TEAEs, n (%) 24 (10) 42 (8.3) 66 (8.7) Any TEAEs by maximum severity, n (%) Mild 50 (20) 91 (18) 141 (19) Moderate 106 (42) 227 (45) 333 (44) Severe 26 (10) 42 (8.3) 68 (9.0) SAEs* 0 (0.0) 3 (0.6) 3 (0.4) TEAEs leading to study drug discontinuation, n (%) 2 (0.8) 7 (1.4) 9 (1.2) Injection site reaction, n (%) 5 (2.0) 16 (3.2) 21 (2.8) Hypersensitivity, n (%) 1 (0.4) 1 (0.2) 2 (0.3) Platelet count decreased, n (%) 4 (1.6) 2 (0.4) 6 (0.8) Hepatic laboratory measures, n (%) ALT or AST ≥ 3X ULN at any post-baseline visit 4 (1.6) 5 (1.0) 9 (1.2) ALT or AST ≥ 5X ULN at any post-baseline visit 2 (0.8) 2 (0.4) 4 (0.5) % = 100 x n/N. *SAE is an adverse event that results in death, is life-threatening or requires hospitalization. There were two SAE CV deaths (cardiogenic shock following acute MI and sudden cardiac death in the setting of extensive underlying CV disease) and one death due to chronic myelomonocytic leukemia; all were attributabl e to pre-existing CV or hematologic disease and were assessed as unrelated to study treatment. Note: Patients with multiple events are counted only once within a category. Glycemic control –related TEAEs, included diabetes mellitus inadequate control, diabetes mellitus, type 2 diabetes mellitus, hyperglycemia, blood glucose increased, HbA1c increased, glucose tolerance impaired, glucose urine present/glycosuria, and insulin resistance, Injection site: reaction TEAEs included pain, erythema, reactions, bruising, discomfort, hypersensitivity, inflammation, pruritis, and administration site: erythema, pain, reaction by system organ class and preferred term.
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| 26 No Worsening of HbA1c Over Time HbA1c, glycosylated hemoglobin; SEM, standard error of mean. 0 3 6 9 12 4 5 6 7 8 Visit (Month) Mean (± SEM) HbA1c (%) 0 3 6 9 12 -1.0 -0.5 0.0 0.5 1.0 Visit (Month) Mean (± SEM) Change from Baseline in HbA1c (%) Glycemic Control: HbA1c (All Patients) Mean (±SEM) Absolute Value Over Time Glycemic Control: HbA1c (All Patients) Mean (±SEM) Absolute Change from Baseline SHASTA-3 Plozasiran 25 mg SHASTA-3 Placebo SHASTA-4 Plozasiran 25 mg SHASTA-4 Placebo
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| 27 Conclusions › Plozasiran administered every 3 months reduced TG and AP events in patients with sHTG on conventional background therapy and diet › TG reductions of ~80% were evident at 3 months and sustained over 12 months, with an associated in reduction in risk of AP of ~80% › >90% of patients treated with plozasiran achieved TGs below 5.6 mmol/L (500 mg/dL) and >50% achieved TGs below 1.7 mmol/L (150 mg/dL) › Plozasiran reduced the risk of AP across the TG spectrum including the high-risk subgroups; by 91% in all patients with a history of AP and by 100% in the highest risk sub - group, (TG ≥10 mmol/L [880 mg/dL] + history of AP] › No new safety signals identified, consistent with prior experience › The findings support the value of APOC3-targeted therapy with plozasiran for preventing AP in sHTG
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| 28 Disclosures › GF Watts reports grants and/or honoraria from Amgen, Novartis, Arrowhead, Esperion, Astra Zeneca, Pfizer, Novo Nordisk, Silence Therapeutics, CSL Seqirus, and Sanofi-Regeneron. CM Ballantyne reports Grant/Research Support: Abbott Diagnostic, Akcea, Amgen, Arrowhead, lonis, Merck, New Amsterdam, Novartis, Novo Nordisk, Roche Diagnostic, NIH, AHA, ADA (all paid to institution, not individual) and Consultant: 89Bio, Abbott Diagnostics, Amarin, Amgen, Arrowhead, AstraZeneca, Denka Seiken, Eli Lilly, Esperion, Genentech, lllumina, lonis, Merck, New Amsterdam, Novartis, Novo Nordisk, Roche Diagnostic. AB Echevarria reports honoraria for lectures/advisory boards from Novo Nordisk, Novartis, Amgen, Sanofi, Eli Lilly, Daiichi Sankyo, Sobi, Ultragenyx, and the Spanish Society of Arteriosclerosis; payment for expert testimony from Menarini; travel support from Ferrer, Ultragenyx, Chiesi; Member of the board of directors of the Spanish Society of Arteriosclerosis (until 2024).RS Rosenson reports grant/research support from (all paid to institution, not individual): Amgen, Arrowhead, Novartis, Eli Lilly, Regeneron; consulting fees from Amgen, Arrowhead, CRISPR Therapeutics, Eli Lilly, Lipigon, Novartis, Precision Biosciences, Regeneron, Ultragenyx, Verve; non-promotional speaking fee from Amgen and Kowa; other support from MediMergent, LLC (significant); and is an UpToDate, Inc. stock shareholder (significant).S Subramanian reports grants from Arrowhead and Eli Lilly; consulting/advisory fees from Ionis and Abbott Diabetes Care; participation on a Data Safety Monitoring Board for Ionis and New Amsterdam Pharma N Lepor reports research grants from Arrowhead, Ionis, Amgen, Novartis, AstraZeneca, Merck, Novo Nordisk, Kardigan, Genentech, Boehringer Ingelheim, Bayer (all paid to institution, not individual) and speaker fees from Ionis, Amgen, AstraZeneca, Novo Nordisk, Bayer, Regeneron. A Bajaj reports research grants from Arrowhead, Amgen, Ionis, New Amsterdam Pharma, Eli Lilly, Novartis, Alexion (all paid to institution, not individual); honoraria/speaker fees from Chiesi, Arrowhead, Ionis; Board Member for National Lipid Association, National Triglyceride Association. J Goldberg received research funding from NHLDI, and reports being a consultant for Akcea-Ionis, and Arrowhead Pharmaceuticals. A Gallo received funding from Amgen, Arrowhead, Bio89, Ionis, and Sanofi-Regeneron. A.G. has also received honoraria for board, conferences or congresses from Akcea, Amarin, Amgen, AstraZeneca, Chiesi, Lilly, MSD, Novartis, Sanofi-Regeneron, Servier, Viatris, and Ultragenyx. R Scott reports travel support for continuing medical education from Christchurch Hospital. M Saxena reports research grants/aid from NIHR, MSD, Recor Medical, Ablative Solutions all paid to institution, not individual); advisory/consulting/speaker fees from AstraZeneca, Arrowhead, Alnylam, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Novartis, Mineralys Therapeutics, Sanofi, Vifor Pharma, Recor Medical, Marea Therapeutics, Menarini, MSD, IQVIA, PPD; travel support from AstraZeneca, Mineralys, Novartis; Board/committee membership: British & Irish Hypertension Society Executive Committee member (Honorary) and CV Research Specialty Lead North London NIHR (funding to institution) A Baass received research grants from Akcea, Amgen, Astra Zeneca, Fondation Leducq, Fondation Yvan Morin, Merck Frosst, and Sanofi and has participated in clinical research protocols from Acasti Pharma Inc., Akcea, Amgen, Arrowhead Pharmaceuticals, Astra Zeneca, Ionis Pharmaceuticals, Inc., Isis Pharmaceuticals, The Medicines Company, Merck Frosst, Novartis, Pfizer, Regeneron Pharmaceuticals Inc., and Sanofi. A.M. has served on advisory boards and received honoraria for symposia from Akcea, Amgen, and Sanofi. R Fu, L Aiyer,J Hellawell, and J Hamilton are all current employees of Arrowhead Pharmaceuticals. D Gaudet reports grants and/or honoraria from Alnylam, Amgen, Arrowhead, AstraZeneca, Boehringer-Ingelheim, CRISPR Therapeutics, Dalcor Pharma, Eli Lilly, Esperion, Ionis, Kowa, Novartis, Pfizer, Regeneron, Sanofi, Ultragenyx and Verve Therapeutics. J Smith, V Blaha, JL Diaz Dalco, J Li report no conflicts of interest.
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SHASTA-3 and SHASTA-4 Discussion Børge Nordestgaard, MD Copenhagen University Hospital European Society of Cardiology Congress 2026
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Discussant review - SHASTA-3/4 Børge G Nordestgaard Copenhagen University Hospital University of Copenhagen
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31 0 150 500 880 Triglycerides 64 % 34 % 1:100 Nordestgaard BG 2026 Population distribution 1:million Familial Chylomicronaemia Syndrome Severe hypertriglyceridaemia mg/dL 0 1.7 5.7 10 mmol/L Olezarsen Plozasiran Volanesorsen Olezarsen Plozasiran
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0 150 500 880 Triglycerides 1:100 Nordestgaard BG 2026 1:million Severe hypertriglyceridaemia mg/dL 0 1.7 5.7 10 mmol/L Olezarsen Plozasiran Volanesorsen Olezarsen Plozasiran Acute pancreatitis reduction Familial Chylomicronaemia Syndrome
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Side effects • Worsening glycemic control (14% vs. 9%) • Low drug discontinuation • More follow-up needed Nordestgaard BG 2026
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SHASTA-3 and SHASTA-4 baseline : N=757 with severe hypertriglyceridaemia ≥ 5.7 mmol/L (500 mg/dL) 21% acute pancreatitis (AP)32% ASCVD 59% diabetes N=400 acute pancreatitisN=2000 ASCVD 3.4 million individuals without ASCVD/AP nationwide in Denmark 2008-21: N=29,000 with severe hypertriglyceridaemia ≥ 5.7 mmol/L (500 mg/dL) Incidence per 1000 person-years 18 2 Nordestgaard BG 2026 unpublished x9x5
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A huge unmet medical need: Severe hypertriglyceridaemia causing acute pancreatitis and ASCVD Now we have efficient therapies: ApoC3 inhibition to lower triglycerides and acute pancreatitis Nordestgaard BG 2026 Clinical implication Focus on preventing ASCVD needed
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Plozasiran Commercialization Efforts Andy Davis, MBA Senior Vice President, Cardiometabolic Franchise European Society of Cardiology Congress 2026
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37 Multiple Groups of Patients with Elevated TGs Have Been Studied in Plozasiran Clinical Trials For investor communication only. Not for use in product promotion Source: Nemeth, Journal of Clinical Medicine 2022; Rabacchi, Atherosclerosis 2015; Company Estimates High-Risk SHTG Severe Hypertriglyceridemia (SHTG) SHTG • TGs ≥ 500 mg/dL • >3+ million people • Elevated Risk of AP High-Risk SHTG • TGs ≥ 880 mg/dL or ≥ 500 mg/dL With Prior AP History • ~1 million people • Higher Risk of AP FCS (Genetic or Clinical) • Persistently Elevated TGs ≥ 880 mg/dL • Prevalent Prior History of AP • Potentially 6500+ people • Extremely High Risk of AP FCS (Genetic or Clinical) Figure Not to Scale US Market Size Estimates
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38 TG Reduction Goal Attainment AP Risk Reduction Safety Profile Dosing Simplicity The Value Proposition of Plozasiran Across These Patient Groups Has Been Consistent and Regarded as Best-in-Class For investor communication only. Not for use in product promotion 1. -27% placebo; 2. At month 12; 3.Relative to placebo; 4.Watts et al. EHJ 2026 and Tryngolza USPI • Deep: Reduction of ~80% compared to baseline1 • Sustained: Maintained throughout the treatment period • Over 90% of plozasiran-treated patients reached levels less than 500 mg/dL2 • Statistically significant reduction in risk of developing acute pancreatitis Favorable safety profile • Convenient 25-mg dose every three-months • No titration required • No hypersensitivity • No clinically meaningful change in platelets • No meaningful elevation in liver enzymes or liver fat3 • Change in HbA1c consistent with APOC3i class4 Delivering on What is Important to Patients, Physicians, and Payers
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39 Our Initial Launch Focus Will Be The High-Risk sHTG Segment For investor communication only. Not for use in product promotion 500 – 880 mg/dL ≥ 880 mg/dL No Prior History of AP ~2.6M ~0.7M 3.3 Prior History of AP ~0.1M ~0.1M 0.2 2.7 0.8 3.5 Recurrent hospitalizations for severe abdominal pain without other explainable cause; OR Family history of hypertriglyceridemia- induced pancreatitis Recurrent episodes of acute pancreatitis not caused by alcohol or cholelithiasis; OR childhood pancreatitis The Shaded Quadrants Represent the Highest Clinical Urgency and Payer Willingness to Pay Estimated US Adult Population (M) Potential Clinical FCS Source: Company estimates
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40 The Number Needed to Treat (NNT) with Plozasiran in the High-Risk Segment is Compelling and Supports This Launch Focus For investor communication only. Not for use in product promotion 500 – 880 mg/dL ≥ 880 mg/dL No Prior History of AP Prior History of AP NNT = 9* In the High-risk Segments, You Need to Treat 3–9 Patients for 1 Year with Plozasiran to Prevent 1 AP Event NNT for Select Segments *Source: Arrowhead Data on File
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41 The Number Needed to Treat (NNT) with Plozasiran in the High-Risk Segment is Compelling and Supports This Launch Focus For investor communication only. Not for use in product promotion 500 – 880 mg/dL ≥ 880 mg/dL No Prior History of AP Prior History of AP NNT = 3 In the High-risk Segments, You Need to Treat 3–9 Patients for 1 Year with Plozasiran to Prevent 1 AP Event NNT for Select Segments *Source: Arrowhead Data on File
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42 We Are Targeting Over 20,000 Healthcare Professionals in the U.S. at Launch For investor communication only. Not for use in product promotion HCPs Identified Across 4 Specialties Who Primarily Treat SHTG ENDOCRINOLOGISTS LIPIDOLOGISTS PREVENTIVE CARDIOLOGISTS INTERNAL MEDICINE/PRIMARY CARE High-Risk SHTG patients in the U.S.~1M
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43 Our Commercialization Efforts Are Already Very Advanced For investor communication only. Not for use in product promotion Medical Commercial Patient Services Regulatory Day 1 Launch Medical Education and Communication strategy developed and executing Marketing and Market Access strategy developed and executing compliantly on key go-to-market activities Expansion and optimization of distribution and patient services well underway Regulatory interactions planned in the near future Patient, provider, and payer Day 1 readiness Key Launch Readiness Activities
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Key Takeaways Vince Anzalone, CFA Senior Vice President, Investor Relations European Society of Cardiology Congress 2026
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45 Key Takeaways For investor communication only. Not for use in product promotion Plozasiran demonstrates an attractive profile and consistent safety and tolerability Compelling value proposition for physicians, patients, and payers with a low number needed to treat (NNT) to prevent 1 AP event in one year of treatment • NNT of 24 in overall sHTG study population • NNT of 3 in patients with a prior history of AP sNDA on schedule for 2026 with priority review voucher potentially accelerating review Launch readiness efforts well underway • If approved, sHTG represents a potential $3-4 billion opportunity
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46 What’s Next in Arrowhead’s Cardiometabolic Pipeline Lipid Disorders, Including FCS, sHTG, Mixed Hyperlipidemia, and HoFH, Are Characterized by a Spectrum of Elevated Levels of TGs and/or Cholesterol1-12 For investor communication only. Not for use in product promotion ASCVD, atherosclerotic cardiovascular disease; FCS, familial chylomicronemia syndrome; HeFH, heterozygous familial hypercholesterolemia; HoFH, homozygous familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; sHTG, severe hypertriglyceridemia; TG, triglyceride; TRL, triglyceride-rich lipoprotein. *REDEMPLO (plozasiran) is approved to reduce TGs in FCS in US, EU, Canada, Australia, and China, but investigational plozasiran has not been reviewed or approved to treat sHTG in any countries 1. Malick WA, et al. J Am Coll Cardiol. 2023;81(16):1646-1658. 2. Larouche M, et al. Curr Atheroscler Rep. 2023;25(12):1101-1111. 3. Nordestgaard BG, et al. Lancet. 2014;384(9943):626-635. 4. Mach F, et al. Eur Heart J. 2020;41(1):111-188. 5. Lloyd-Jones DM, et al. J Am Coll Cardiol. 2022;80(14):1366-1418. 6. McGowan MP, et al. J Am Heart Assoc. 2019;8(24):e013225. 7. Yang Z, et al. Front Cardiovasc Med. 2022;9:913977. 8. Romandini A, et al. Pharmaceuticals (Basel). 2023;16(2):176. 9. Virani SS, et al. J Am Coll Cardiol. 2021;78(9):960-993. 10. Gaudet D, et al. N Engl J Med. 2014;371(23):2200-2206. 11. Berberich AJ, et al. Endocr Rev. 2022;43(4):611-653. ANGPTL3/ PCSK9 Residual risk of ASCVD is related to elevated TGs or cholesterol -Rare Disorder- HoFH LDL-C ≥400 mg/dL HeFH LDL-C ≥190 mg/dL Mixed Hyperlipidemia Elevated TRLs, remnant cholesterol, LDL sHTG TG ≥500 mg/dL -Rare Disorder- FCS TG ≥880 mg/dL Risk of acute pancreatitis is associated with severely elevated TG levels Elevated TG APOC3 ARO-DIMER-PAInvestigational Zodasiran REDEMPLO (plozasiran*) Elevated LDL
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47 Multiple Potential Commercial Launches in Cardiometabolic For investor communication only. Not for use in product promotion Potential Independent Launches Late-Stage Partnered Program Olpasiran is a small interfering RNA (siRNA) that lowers lipoprotein(a), also known as Lp(a). It is being investigated by Amgen in Phase 3 studies for the treatment of atherosclerotic cardiovascular disease /MASH
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48 Questions? Answers. For investor communication only. Not for use in product promotion