Arrowhead Pharmaceuticals : TIDES USA 2024 TIDES 2024 AdiposeTIDES 2024 ARO-SOD1

TIDES USA 2024

Novel TRiM Platform for Delivery of RNAi Therapeutics to Adipose Tissue

Tao Pei, Ph.D.

Senior Vice President, Chemistry

Arrowhead Pharmaceuticals

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 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, enter into collaborations and achieve other projected milestones, rapid technological change 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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TRiM Platforms Drive Robust Pipeline for Multiple Tissue Types

Liver	Lung	Skeletal	CNS	Adipose	Ocular
		Muscle
9	3	2	1	1	1
Clinical	Clinical	Pre/Clinical	Preclinical	Preclinical	Preclinical
Programs	Programs	Programs	Program	Program	Program

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TRiM Platform: Targeted RNAi Molecule

A modular system with:

• Unique RNAi chemistry insights and expertise
• Powerful platform technology to maximize activity and stability employing:
• • Algorithmic approach to sequence selection and design
  • Stabilization chemistry
  • Targeting ligand
  • Linker chemistry
  • PK and PD enhancers

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Agenda

• TRiM Adipose Platform
• Platform development
• Platform efficacy in mouse and NHP
• Tissue selectivity and distribution profile
• Safety profile

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Adipose Tissue Is Therapeutically Relevant to Metabolic Diseases

• Largest endocrine organ in the body
• Produces/secretes numerous adipokines (messengers) which regulate numerous physiological functions
• Adipose dysfunction has been associated with:
• • Insulin resistance
  • Type 2 diabetes (T2D)
  • Dyslipidemia
  • Hyperinsulinemia
  • Cardiovascular disease
  • Cancers
• Adipose tissue-related research has greatly increased over the last 10 years as a result of its roles in regulating metabolic functions

Luo, L. & Liu, M. (2016). Adipose tissue in control of metabolism. Journal of Endocrinology, 231. R77-R99.

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Adipose Tissue Is Therapeutically Relevant to Metabolic Diseases

• Largest endocrine organ in the body
• Produces/secretes numerous adipokines (messengers) which regulate numerous physiological functions
• Adipose dysfunction has been associated with:
• • Insulin resistance
  • Type 2 diabetes (T2D)
  • Dyslipidemia
  • Hyperinsulinemia
  • Cardiovascular disease
  • Cancers
• Adipose tissue-related research has greatly increased over the last 10 years as a result of its roles in regulating metabolic functions

Target Gene mRNA Expression

Mouse Adipose Tissue

1 mpk (SC)

Day 15

1.5		0% KD

Expression	1.0
Relative	0.5
	0.0	siRNA
	Saline

• Platform development strategy: targeting Adiponectin (i.e. Adipoq) gene, exclusively expressed in adipocytes
• No target gene knockdown (KD) observed via siRNA alone

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Adipose Tissue Is Therapeutically Relevant to Metabolic Diseases

• Largest endocrine organ in the body
• Produces/secretes numerous adipokines (messengers) which regulate numerous physiological functions
• Adipose dysfunction has been associated with:
• • Insulin resistance
  • Type 2 diabetes (T2D)
  • Dyslipidemia
  • Hyperinsulinemia
  • Cardiovascular disease
  • Cancers
• Adipose tissue-related research has greatly increased over the last 10 years as a result of its roles in regulating metabolic functions

Target Gene mRNA Expression

Mouse Adipose Tissue

1 mpk (SC)

Day 15

1.5		0% KD 35% KD

Expression	1.0
Relative	0.5
	0.0	siRNA	Lipid-siRNA
	Saline
			Conjugate

• Given nature of adipose as lipid storage, lipids chosen to target siRNA to desired tissue
• Lipid-siRNAconjugate shown to enable knockdown (KD) of target gene

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Dual Lipid Platform Outperforms Mono Lipid in Mouse

Serum Adipoq Protein Expression

Mouse

1 mpk (SC)

	1.2
Expression	1.0
0.8
0.6
Relative	0.4
0.2
	0.0
	D1	D8	D15	D1	D8	D15
		Saline			Mono Lipid

• Mono lipid conjugate able to achieve good KD (~60%)

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Dual Lipid Platform Outperforms Mono Lipid in Mouse

Serum Adipoq Protein Expression

Mouse

1 mpk (SC)

	1.2
Expression	1.0
0.8
0.6
Relative	0.4
0.2
								90% KD
	0.0
	D1	D8	D15	D1	D8	D15	D1	D8	D15
		Saline	Mono Lipid		Dual Lipid

• Dual lipid conjugate found to improve KD efficacy

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