Slide 1: 2026 Summer Series of R&D Webinars: Cardiometabolic
2026 Summer Series of R&D Webinars Part |—- Cardiometabolic June 29, 2026 J arrowhead Pharmaceuticals
Slide 2: Safe Harbor Statement
Safe Harbor Statement 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 ma
Slide 3: Agenda
Agenda Topic Presenter Overview of Cardiometabolic Pipeline Vince Anzalone, CFA Arrowhead’s Technology and R&D Process James Hamilton, M.D., MBA Plozasiran (APOC3) Jennifer Hellawell, M.D. Zodasiran (ANGPTL3) Jennifer Hellawell, M.D. ARO-DIMER-PA (PCSK9/APOC3) James Hamilton, M.D., MBA Mixed Hyperli
Slide 4: Cardiometabolic Key Opinion Leader
Cardiometabolic Key Opinion Leader Steven Nissen, M.D. Cleveland Clinic Steven E. Nissen, MD, is Chief Academic Officer for the Heart and Vascular Institute at the Cleveland Clinic, the Lewis and Patricia Dickey Chair in Cardiovascular Medicine and Professor of Medicine at the Lerner College of Medi
Slide 5: Overview of Cardiometabolic Pipeline
Cardiometabolic R&D Webinar June 2026 Overview of Cardiometabolic Pipeline Vince Anzalone, CFA Senior Vice President
Slide 6: Bringing RNA Interference to Patients
Bringing RNA Interference to Patients 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 fa rst Commercial Launch in 2025 F Broad Pipeline Proprietary Platform & Financial R
Slide 7: Active Across Cardiometabolic and TG/LDL Spectrum
Active Across Cardiometabolic and TG/LDL Spectrum Lipid Disorders, Including FCS, sHTG, Mixed Hyperlipidemia, and HoFH, Are Characterized by a Spectrum of Elevated Levels of TGs and/or Cholesterol!-'2 APOC3 Risk of acute Residual risk pancreatitis is of ASCVD associated is related to with severely e
Slide 8: Potential Upcoming Commercial Launches in Cardiometabolic
Potential Upcoming Commercial Launches in Cardiometabolic OBESITY Potential Ind Launches SHTG (2027) FCS (2025) Late-Stage Partnered Pro. * Olpasiran is a small interfering RNA (siRNA) that lowers lipoprotein(a), also known as Lp(a). If is being investigated by Amgen in Phase 3 studies for the treat
Slide 9: Arrowhead's Technology and R&D Process
Cardiometabolic R&D Webinar June 2026 Arrowhead’s Technology and R&D Process James Hamilton MD, MBA Chief Medical Officer and Head of R&D
Slide 10: Arrowhead's Targeted RNAi Molecule (TRIM) Platform
Arrowhead’s Targeted RNAi Molecule (TRIM™) Platform: The Broadest and Most Versatile in the Field TRIM™ also has rules and algorithms to optimize trigger sequence and modification patterns e Activity Characterized by depth & duration of effect ey ; * Ability to unlock previously undruggable CHEMISTR
Slide 11: TRIM Platform Enables Delivery to Seven Cell Types
TRIM™ Platform Enables Delivery to Seven Cell Types Agia) QMO@O@OE Skeletal F Cardio- Liver Lung eee Adipose Ocular myocyte Strong Deep lung Early Early Early Preclinical Preclinical clinical clinical clinical clinical clinical Stage Stage validation validation stage stage validation (RAGE) Arrowhea
Slide 12: Robust Pipeline with Near-term Commercial Opportunities and Long-term Growth
Robust Pipeline with Near-term Commercial Opportunities and Long-term Growth Opportunities For investor communication only. Not for use in product promotion 12
Slide 13: Discovery Capacity Supports Consistent Pipeline Growth
Discovery Capacity Supports Consistent Pipeline Growth Concept to CTA Goal of 12 Months New Discovery Programs Initiated idate N ations & 12 7 10 é 8 5 4 6 3 4 2 2 1 to) to} 2020 2=—-2021 2022 «= 2028S 2024-2025: 2026 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 (1Q) (1Q) f CTA or INDFilings or
Slide 14: Translational Genetics Leveraging Large-Scale Data and AI
Translational Genetics is Leveraging Large-Scale Data and Al for Target Identification and Prioritization Data Identification and Sta’ Curation Modelling q )DECIEHER = Open oe é aS Y BxOBiwia “Ndepmap gnomaD Genomics _ ahd )OmicSofi panda’ Corporation Omics biobank’ IPA & perex | PHARMAPROJECTS. Gor
Slide 15: Plozasiran
Cardiometabolic R&D Webinar June 2026 Plozasiran Jennifer Hellawell, MD Vice President, Clinical Development
Slide 16: Multiple Segments of Patients with Elevated TGs Being Studied
Multiple Segments of Patients with Elevated TGs Being Studied Severe Hypertriglyceridemia (SHTG) H High-Risk SHTG . FCS (Genetic or Clinical) . Figure Not to Scale Source: Nemeth, Journal of Clinical Medicine 2022; Rabacchi, Atherosclerosis 2015; Company Estimates Co) arrowhead Ds For investor commu
Slide 17: Overview of Plozasiran Development Program
Overview of Plozasiran Development Program SUMMIT PROGRAM: PLOZASIRAN (4P0¢3-targeted siRNA) Patient Population Study Name __ Study Objective Status Phase Familial ’ A In adults with FCS and TG 2880 mg/dL (210 mmol/L) (N=75), the study een Chylomicronemia ADALISADE Primary endpoint was to evaluate c
Slide 18: SHASTA-2 and MUIR OLE Study Design
SHASTA-2 and MUIR Open-Label Extension (OLE) Study Design Double-Blind Open-Label Extension Plozasiran 10 mg SHASTA-2: N=54 | MUIR: N=67 § | Plozasiran 25 mg 3 Screening!) | SUASTA-2 N=55| MUIR N&=67 Eig Continuous Plozasiran, 25 mg/Q3M Diet 8 7 a SHASTA-2 N=123 | MUIR N=192 Run-in rs Plozasiran 50
Slide 19: SHASTA-2 and MUIR OLE Baseline Characteristics
SHASTA-2 and MUIR OLE Baseline Characteristics Placebo to Continuous Placebo to Continuous Plozasiran Plozasiran Plozasiran Plozasiran (N=46) (N=123) (N=57) (N=192) ‘Age (years), mean (SD) 56.4 (10.8) 55.8 (11.2) 60.5 (10.1) 63.3 (11.0) Male, n (%) 33 (71.7) 97 (78.9) 32 (56.1) 108 (56.3) Race, Whit
Slide 20: Median Absolute Values in TG in SHASTA-2 and MUIR OLE
Median Absolute Values in TG in SHASTA-2 and MUIR OLE 96% of patients achieved TG<500 mg/dL and 93% of patients achieved TG <150 mg/dL* 63% of patients achieved TG<150 mg/dlL* 4005 _, 1000+ -@® Placebo to plozasiran a -® Placebo to plozasiran 3 -™ Continuous plozasiran 3 —® Continuous plozasiran E E
Slide 21: Kaplan Meier Plot of Time to First Adjudicated AP Event
Kaplan Meier Plot of Time to First Adjudicated AP Event in the SHASTA-2 OLE No Positively Adjudicated AP Events in the OLE Out to 24 Months Ballantyne CM, et al. Am J Prev Cardiol. 2026 Mar 24:27:101523. doi: 10.1016/j.ajpc.2026.101523 For investor communication only. Not for use in product promotio
Slide 22: SHASTA-2 & MUIR OLE Safety Findings
SHASTA-2 & MUIR OLE Safety Findings OLE Safety Consistent With Index Studies, No Clinically Meaningful Changes in HbA1c or Liver Function Ballantyne CM, et al. Am J Prev Cardiol. 2026 Mar 24:27:101523. doi: 10.1016/j.ajpc.2026.101523 For investor communication only. Not for use in product promotion
Slide 23: SHASTA-2 & MUIR OLE Takeaways
SHASTA-2 & MUIR OLE Takeaways Long-term treatment with 25 mg Q3M of plozasiran resulted in sustained and G clinically meaningful reductions in TG across a broad spectrum of HTG through 24 months G Majority of patients achieved TG levels below thresholds for AP risk or below normal thresholds G There
Slide 24: SHASTA-3 and -4 Study Design
SHASTA-3 and -4 Study Design Two Double-Blind, Placebo-Controlled Phase 3 Studies to Evaluate the Efficacy and Safety of Plozasiran (ARO-APOC3) in Adults With Severe Hypertriglyceridemia (SHTG) Key Eligibility Criteria * 18 years or older * Diagnosis of SHTG and prior medical history of fasting TG l
Slide 25: SHASTA-3 and -4 Global Enrollment
SHASTA-3 and -4 Global Enrollment fo arrowhead Pharmaceuticals . For investor communication only. Not for use in product promotion 23 Unique Countries SHASTA-3: 17 countries SHASTA-4: 16 countries 351 Total Sites SHASTA-3: 200 sites SHASTA-4: 151 sites 757 Total Randomizations SHASTA-3: 446 SHASTA-4
Slide 26: SHASTA-3 and -4 Baseline Characteristics
SHASTA-3 and -4 Baseline Characteristics ‘Age (Years), mean (SD) Sex at birth, male n (%) Race, n(%) White Asian Black or African American Other Ethnicity, n (%) Hispanic or Latino Not Hispanic or Latino Region, n (%) North America BMI (kg/m?), mean (SD) Lipid lowering therapy, n (%) Statin Fibrate
Slide 27: Plozasiran Timeline Considerations for SHTG
Plozasiran Timeline Considerations for SHTG G Topline data release Q3 2026 G SHASTA-3/4 medical congress presentation and publication 2H 2026 G SNDA filing planned by end of 2026 OL arrowhead ion only. Not for use in product promotion 7
Slide 28: Zodasiran
Cardiometabolic R&D Webinar June 2026 Zodasiran Jennifer Hellawell, MD Vice President, Clinical Development
Slide 29: HoFH is a Rare But Grievous Disease with High Unmet Need
HOFH is a Rare But Grievous Disease with High Unmet Need HoFH is a Rare But Grievous Disease HoFH Patients at Risk Despite Available Therapies ¢ HoFH patients have untreated O ¢ In CASCADE FH registry, 78% of LDL-C 400-1000 mg/dL, ~ four <> adults and 44% of children with to 10 times normal HoFH had
Slide 30: ANGPTL3 is a Key Regulator of Lipoprotein Metabolism and Clearance
ANGPTL3 is a Key Regulator of Lipoprotein Metabolism and Clearance! Dy ANGPTL3 Vv IDL vy conversion Y LDL Vv Of IDL fo LDL ALPL A Lipolysis AEL A Remodeling Vv production LDLR-related i proteins AA Hepatic remnant 2 clearance Y Defective or deficient LDLR * ANGPIL3 is a hepatocyte expressed regulato
Slide 31: Overview of Zodasiran Development Program
Overview of Zodasiran Development Program m vista. VISTA PROGRAM: ZODASIRAN (ARO-ANG3) Patient Population Study Name_ Study Objective Status Phase ' In adults with TG 21.69-5.65 mmol/L (2150-499 mg/dL) and LDL-C Mixed ©) 31.8 mmol/L (270 mg/dl) (N=204), the primary endpoint was to evaluate Study rat
Slide 32: GATEWAY Phase 2: Zodasiran Reductions in LDL-C and ApoB
GATEWAY Phase 2: Zodasiran Demonstrated Substantial and Durable Reductions in LDL-C and ApoB Throughout the Randomized Treatment Period and OLE LDL-C ANGPTL3 5. Randomized Treatment = =L Open-label Extension 00mg | 300mg Mean (SE) Change from Baseline (mg/dL) RT Oe Mean Percent Change (SE) from Base
Slide 33: YOSEMITE: Study Design
YOSEMITE: Study Design Phase 3 Study to Evaluate the Efficacy and Safety of Zodasiran (ARO-ANG3) in Adolescents and Adults with Homozygous Familial Hypercholesterolemia (HoFH) Key Eligibility Criteria + 212 years of age with a genetic or clinical diagnosis of HoFH on standard of care, maximally tole
Slide 34: YOSEMITE Global Enrollment
YOSEMITE Global Enrollment ee 21 Unique Countries ict : Selected i?) ‘Canada ’ ) - secon OO. ellie Atlantic 47 Total Sites Activated Indian South Ocean Pacific a Atlantic Ocean Ocean ee a 60 Randomizations Planned Oh arrowhead For investor communication only. Not for use in product promotion 34
Slide 35: SPRUCE: Study Design
SPRUCE: Study Design Phase 3 Single-Arm Open-Label Study to Evaluate the Efficacy and Safety of Zodasiran (ARO-ANG3) in Adolescents with Homozygous Familial Hypercholesterolemia (HoFH) i iteri Not Yet Enrolling * Adolescents 12 to <18 years of age who are nonpregnant, nonlactaling, and do not plan t
Slide 36: Zodasiran Next Steps
Zodasiran Next Steps Y Broader pediatric program in development with adolescent-focused study (SPRUCE) anticipated to randomize its first patient soon G YOSEMITE full enrollment anticipated in Summer 2026 G Completion of 12 months double blind portion of study in Summer 2027 G Zodasiran NDA planned
Slide 37: ARO-DIMER-PA
Cardiometabolic R&D Webinar June 2026 ARO-DIMER-PA James Hamilton MD, MBA Chief Medical Officer and Head of R&D
Slide 38: Single RNAi Molecule to Silence Two Genes
Single RNAi Molecule to Silence Two Genes Single Chemical Entity to Silence Two Gene Targets * Regulatory advantages over two co-dosed drugs * Two siRNAs internalized during one receptor turnover For investor communication only. Not for use in product promotion 38
Slide 39: ApoC3/PCSK9 siRNA Dimer for Lowering CVD Risk in Mixed Hyperlipidemia
ApoC3/PCSK9 siRNA Dimer for Lowering CVD Risk in Mixed Hyperlipidemia Patients APOC3 regulates triglyceride transport and uptake * Competitively inhibits lipoprotein lipases * Inhibits uptake of TG-rich particles KD of APOC3 + Increase uptake and lipolysis of circulating TG-rich particles + Lower ri
Slide 40: ARO-DIMER-PA to Silence PCSK9 and APOC3
ARO-DIMER-PA to Silence PCSK9? and APOC3 Monomer PCSK9 (3 mpk) + Monomer APOC3 (3 mpk) “= ARO-DIMER-PA (6 mpk) (Cease weeeceereereesen 80% KD +» 80% KD Mean + SEM T_T _T_T_T_T TT Relative Serum PCSK9 (Norm'd to mean predose) Relative Serum APOC3 (norm'd to mean predose) T TT T_T T_T T_T Pw SO & LD w
Slide 41: Pharmacologic Effects of ARO-DIMER-PA in Dyslipidemic Monkeys
Pharmacologic Effects of ARO-DIMER-PA Lowering Lipids in Dyslipidemic Cynomolgus Monkeys Non-HDL Cholesterol LDL Cholesterol Triglycerides 200 150: 500- non-HDLc (mg/dL) LDLe (mg/dL) Triglycerides (mg/dL) Mean + SEM TT t—1—T T_T T—T tse peeapeeneesy 70 84 98 112 14 0 14 28 42 S6 70 84 98 112 14° 0 1
Slide 42: ARODIMERPA-1001 Study Design (Part 1/Part 2)
ARODIMERPA-1001 Study Design (Part 1/Part 2) Part 1 Single Ascending Dose (SAD): Part 2 Multiple Ascending Dose (MAD): Subjects with Mixed Hyperlipidemia Subjects with Mixed Hyperlipidemia Screening Day 1 (Baseline) Week 24 (EOS) Screening Day 1 (Baseline) Week 12 Week 36 (EOS) (Day -35 to-1), (Day
Slide 43: ARO-DIMER-PA Progress and Timelines
ARO-DIMER-PA Progress and Timelines Y SAD cohorts fully enrolled by mid to late summer G Full enrollment in Q3 2026 G Anticipate topline data release in Q3 2026 OL arrowhead ion only. Not for use in product promotion 43
Slide 44: Mixed Hyperlipidemia, ASCVD, and the Promise of ARO-DIMER-PA
Cardiometabolic R&D Webinar June 2026 Mixed Hyperlipidemia, ASCVD, and the Promise of ARO-DIMER-PA Steven Nissen, MD Cleveland Clinic
Slide 45: Mixed Hyperlipidemia
Mixed Hyperlipidemia Steven E. Nissen MD MACC Chief Academic Officer, Heart, Vascular and Thoracic Institute Cleveland Clinic i C5Research
Slide 46: What Is Mixed Hyperlipidemia?
What Is Mixed Hyperlipidemia? Mixed hyperlipidemia is the simultaneous elevation of LDL-C and triglycerides — frequently accompanied by reduced HDL-C. * Distinct from isolated hypercholesterolemia (LDL-C alone) or isolated hypertriglyceridemia (TG alone). * Clinical hallmark: increased number of cir
Slide 47: The Atherogenic Lipid Triad
The Atherogenic Lipid Triad TG-Rich Remnants Hepatic VLDL overproduction and chylomicron remnants accumulate; small enough to penetrate the arterial wall and are readily retained. Small, Dense LDL CETP-mediated exchange of triglyceride for cholesteryl ester yields LDL particles that are more easily
Slide 48: Prevalence — General Population
Prevalence — General Population Hypercholesterolemia Hypertriglyceridemia (TC 2240 mg/dL) (TG 2200 mg/dL) 11.5% 10.4% ~12.05M U.S. adults] | ~10.84M U.S. adults NHANES 2007-2018 representing 104.4M U.S. residents. ° Prevalence varies by race, ethnicity and Sex ¢ Mexican-American highest hypertriglyc
Slide 49: Prevalence — Genetic & High-Risk Subgroups
EPIDEMIOLOGY Prevalence — Genetic & High-Risk Subgroups Familial combined hyperlipidemia (FCH): The most common inherited dyslipidemia - the genetic form of mixed hyperlipidemia — more common than familial hypercholesterolemia (~0.3-0.4% of the population). ¢ Polygenic disorder driven by hepatic ove
Slide 50: Residual ASCVD Risk Despite Statin Therapy
Residual ASCVD Risk Despite Statin Therapy 0 0 0 DYSlipidemia International Study 48 %o 38 %o 26 vo (DYSIS) — >22,000 statin-treated not at LDL-C elevated patients with established or high- goal triglycerides low HDL-C risk CVD (Europe & Canada) EURIKA (primary prevention) Why LDL-C control isn't en
Slide 51: Acute Pancreatitis Risk
Acute Pancreatitis Risk Severe hypertriglyceridemia (TG 2500 mg/dL) occurs in roughly 1-1.7% of the population and is the third most common cause of acute pancreatitis, after gallstones and alcohol. 18 16 14 | 12 10 Approx. risk of pancreatitis (%) oN FD © 4 1 TG >500 TG >1000 TG >1771 mg/dL mg/dL m
Slide 52: Percent of Population with LDL-C >190 mg/dL Untreated and Unaware
Percent of Population with LDL-C >190 mg/dL Untreated and Unaware 80% 70% | NHANES Survey Data 60% | Percent 50% + Unaware 39.5% 39.7% Untreated | CaS apd 30% 4 26.8% 20% 4 10% 4 0% 2001-2 2005-06 2009-10 2013-14 2017-20 Survey Year JAMA Cardiol. 2023;8(12):1185-1187.
Slide 53: Potential Role of Arrowhead siRNA Dimer for PCSK9 and ApoC3
Potential Role of Arrowhead SiRNA Dimer for PCSK9 and ApoC3 • Both PCSK9 (e.g. inclisiran) and ApoC3 (e.g. plozasiran) validated targets for LDL-C and triglycerides, respectively. • Simultaneous and durable reductions in LDL-C ~50% and triglycerides ~70% with infrequent injections (enhanced adherenc
Slide 54: Clinical Take-Home Points
CLINICAL TAKE-HOME POINTS 01 Common, underrecognized Co-elevated LDL-C and TG affect roughly 1 in 10 U.S. adults at the population level, and the genetic phenotype (FCH) reaches 10—40% in coronary and MI cohorts. 02 Drives residual ASCVD risk TG-rich remnants and small dense LDL continue to promote
Slide 55: Key Takeaways
Cardiometabolic R&D Webinar June 2026 Key Takeaways Vince Anzalone, CFA Senior Vice President
Slide 56: Key Takeaways
Key Takeaways ao, Arrowhead's cardiometabolic pipeline includes multiple promising programs across ( ) the TG/LDL spectrum and building commercial to support complementary assets with similar call points Gi Potential for multiple independent and partner launches over coming years ~ Building on the m
Slide 57: Questions?
“~\ Questions? () » Answers. Pharmaceuticals