Arrowhead Pharmaceuticals : EAS 2025 GATEWAY

Published: 2025-05-07 06:17:22 ET ARWR

Published on 05/07/2025 at 06:17

Zodasiran (ARO-ANG3), an Investigational RNAi Therapeutic, Demonstrates Profound and Durable Reductions in LDL-Cholesterol and Other Atherogenic Lipoproteins in Patients with HoFH; GATEWAY Final Results

AUTHORS: Raal F, Bergeron J, Gaudet D, Rosenson RS, Sullivan D, Turner T, Fu R, Muhsin, M,

Hellawell J, Hamilton J, Hegele RA, Ballantyne CM, Knowles JW1, Leeper NJ, Goldberg I, Watts G F

No, nothing to disclose

Yes, please specify:

Company Name

Honoraria/ Expenses

Consulting/ Advisory Board

Funded Research

Royalties/ Patent

Stock Options

Ownership/ Equity Position

Employee

Other (please specify)

Frederick J Raal

AUTHORS: Raal F, Bergeron J, Gaudet D, Rosenson RS, Sullivan D, Turner T, Fu R, Muhsin, M, Hellawell J, Hamilton J, Hegele RA,

Ballantyne CM, Knowles JW1, Leeper NJ, Goldberg I, Watts G F

Zodasiran

▼ ANGPTL3

▼ IDL ▼ LDL

▼ VLDL

▼ conversion of IDL to LDL

ANGPTL3 is a hepatocyte expressed regulator of lipid and lipoprotein metabolism with multiple potential modes of

▲ LPL

▲ EL

▲ Lipolysis

▲ Remodeling

LDLR-related proteins

Liver

▲ ▲ Hepatic remnant clearance

Defective or

deficient LDLR

▼ production

action, including inhibition of lipoprotein lipase (LPL) and endothelial lipase (EL)1,2

ANGPTL3 loss-of-function variants lead to enhanced LPL and EL activity, resulting in:

▼ LDL-C, TG, VLDL-C/

remnant-C, and HDL-C3-5

▼ Risk of ASCVD3,4,6

No known adverse phenotype is associated with genetic deficiency in ANGPTL33,4

Figure adapted from: Watts G, et al. Eur Heart J. 2024;45:2435-2438.; 1. Adam, et al. J Lipid Res. 2020;61(9): 1271-86. 2. Rosenson. J Lipid Res. 2021:62:100060. 3. Dewey, et al. N Engl J Med. 2017;377 (3):211-21. 4. Minicocci, et al. J Lipid Res. 2013;54(12): 3481-90. 5. Musunuru, et al. N Engl J Med. 2010; 363(23):2220-7. 6. Stitziel, et al. J Am Coll Cardiol. 2017; 69(16):2054-63. ▼=Reductions in; ANGPTL3, angiopoietin-like protein 3; ASCVD, atherosclerotic cardiovascular disease; EL, endothelial lipase; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; LDLR, low-density lipoprotein receptor; LPL, lipoprotein lipase; remnant-C, remnant cholesterol; VLDL, very low-density lipoprotein.

Arrowhead's Targeted RNAi Molecule (TRiM ) technology leverages the RNAi mechanism

RNAi is a natural process that uses short fragments of RNA molecules to interfere with mRNA translation into associated proteins

High Specificity:

Gene specific silencing

Potent Activity: Deep and consistent silencing of target genes

Stabilization

ASGPR

Receptor recycling

Endosomal escape

mRNA

Sequence-specific pairing to target

chemistries

siRNA

siRNA conjugate

Cellular uptake

pH drop

RISC

loading Guide strand

Passenger strand

Passenger strand cleavage

mRNA

RISC

complex remains active

mRNA is

degraded

Infrequent Dosing: Long tissue PK/PD, on target effect

Safety: Minimal off target adverse effects due to targeted delivery (GalNAc) and sequence specificity

Linker chemistries

GalNac targeting ligands

Hepatocyte Cytoplasm

Late

endosome

siRNA is degraded

RISC = RNA-induced silencing complex

Randomized Treatment

Open-label Extension†

Zodasiran extension 300 mg ➩ 200 mg

Zodasiran 300 mg N=G

Zodasiran extension 200 mg continuous

Zodasiran 200 mg N=G

RT OLE

Screening (8 weeks)

Months

0 1 2 3 4 5

6 7 8

9 1 3 6

9 12 15 18 21 24

Study Objectives

To evaluate safety and efficacy of zodasiran in patients with HoFH, and to explore optimal dosing

Primary Endpoint:

% change in LDL-C

Study Population

HoFH confirmed by genetic testing or clinical diagnosis

Fasting LDL-C >2.6 mmol/L at

screening

On stable low-fat diet, lipid-lowering standard of care (including apheresis), statins, ezetimibe +/- PCSK9 inhibitors

Key Endpoints*

Primary endpoint: % change from to Week 24 in fasting LDL-C (UC)

Key secondary PD endpoints:

- Percent and absolute change from baseline in LDL-C, ANGPTL3, total ApoB, HDL-C, TGs

and non-HDL-C at each scheduled assessment (fasting)

Safety

Randomization

18 eligible HoFH patients randomized to receive 200 mg or 300 mg zodasiran SC on Day 1 and Week 12

Open Label Extension (OLE)

All patients were eligible to enroll in the OLE at the end of the study

*All samples taken after ≥10 hour fast. ANGPTL3, angiopoietin-like 3; † The open-label extension was terminated early due to sponsor considerations; however, nearly all patients completed at least one year of follow-up. ApoB, apolipoprotein B; ARO-ANG3, zodasarin; BL, baseline; HDL-C, high density lipoprotein cholesterol; HoFH, homozygous familial hypercholesterolaemia; LDL-C, low density lipoprotein cholesterol; non-HDL-C, non-high-density lipoprotein cholesterol; OLE, open label extension period; RT, randomized treatment period; SC, subcutaneous; TG, triglyceride; UC, preparative ultracentrifuge.

Disclaimer

Arrowhead Pharmaceuticals Inc. published this content on May 07, 2025, and is solely responsible for the information contained herein. Distributed via Public Technologies (PUBT), unedited and unaltered, on May 07, 2025 at 10:15 UTC.