Arrowhead Pharmaceuticals : ECO2025 ALK7

Published: 2025-05-12 16:03:11 ET ARWR

Published on 05/12/2025 at 16:03

Arrowhead Pharmaceuticals Inc., Madison, WI, USA

While incretin-based therapies are the current frontline pharmacotherapeutics for obesity and metabolic outcomes, issues concerning significant loss of lean mass, adverse GI events at high dose levels, and disproportional fat mass gain after cessation of the therapies remain a challenge for many patients

Human genetic studies support ALK7 as a therapeutic target with pLOF ALK7 variants associated with 1) reduced WHRadjBMI, 2) protection from type 2 diabetes, 3) reduced risk of cardiovascular disease

ALK7 signaling suppresses lipolysis, increasing adipocyte size and lipid content

We evaluated the potential therapeutic benefits of ALK7 silencing by siRNA designed to specifically target adipose tissue

ALK7 mRNA silencing % Body weight change

Glycerol NEFA Ketones

qPCR of lipolysis-related gene panel in adipose tissue

iWAT pgWAT

Relative ALK7 mRNA

2.0

1.5

1.0

0.5

-80%

-41%

Saline 80

ALK7 siRNA

% BW change

40 ** **

****

Saline

ALK7 siRNA

500

Free Glycerol (mmol/L)

400

300

200

100

✱✱✱✱

Pre Post Pre Post

3.5

Non-esterified free fatty acids (mmol/L)

3.0

2.5

2.0

1.5

1.0

0.5

0.0

✱✱✱✱

Pre Post Pre Post

4.5

beta-hydroxybutyrate (mmol/L)

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0.0

✱✱✱✱

Pre Post Pre Post

Lipolytic genes in iWA

Relative mRNA levels

Adrb3 Atgl Cgi-58 Hsl Fabp4

Relative mRNA levels

Adrb3 Atgl Cgi-58 Hsl Fabp4

Saline

ALK7 siRNA

0.0

iWAT pgWAT

1 2 3 4 5 6 7 8 9 1011 1213 1415 16

Serum collected prior to and 30 min after challenge with CL316,243, a β3-adrenergic receptor agonist (IP, 1 mg/kg)

Animals (N=10/group) with reduced ALK7 expression had increased circulating levels of glycerol, NEFAs, and ketones (Mean±SEM) and exhibited upregulation in the expression of lipolytic genes

Weeks post first dose

Body composition analysis by DEXA imaging

Fat mass Lean mass

****

30 40

130

O2expenditure (ml/h/kg)

120

O2expenditure Heat production

Heat production (Kcal/h/kg)

*** 0.6

***

At week 8, energy expenditure measurements (Mean ±SEM) were obtained from C57Bl/6 DIO mice (N=10/group) caged in a TSE Phenomaster system over 2 dark and 1 light cycle. ALK7 siRNA treated group exhibited:

Increased levels of O2consumption and heat production

No change in food intake

Saline

Fat Mass (g)

Lean Mass (g)

20 -50%

0 0

Saline ALK7 siRNA

110

100

***

Light phase Dark phase

0.5

0.4

0.3

0.2

0.1

0.0

Light phase Dark phase

ALK7 siRNA

C57Bl/6 DIO mice (male, age = 18 weeks at initiation) received chronic treatment with a mouse surrogate ARO-ALK7 (3 mg/kg weekly), which resulted in:

ALK7 mRNA silencing efficacy of 80% in inguinal white adipose tissue and 40% in perigonadal white adipose tissue at study terminus (week 16)

A significant suppression of up to 39% body weight reduction relative to saline controls

Approximately 50% reduction in fat mass with preservation of lean mass by DEXA imaging analysis

At study terminus, neutral lipid contents in the livers of the animals were analyzed. ALK7 siRNA treated animals demonstrated greater reduction in hepatic lipid accumulation by:

Triglyceride concentration via biochemical assay

Histologic analysis using liver sections stained with hematoxylin and eosin (H&E)

Liver Triglycerides H&E staining

Saline ALK7 siRNA

Triglyceride (mg/dL)

2000

1500

✱✱✱

1000

500

Saline ALK7 siRNA

5x 5x

%Body weight change Body composition by DEXA

Fat mass

C57Bl/6 DIO mice (male, age = 20 weeks) were treated with either 1) saline weekly, 2) ALK7 surrogate siRNA 3 mg/kg weekly,

3) tirzepatide (0.21 mg/kg QD), 4) tirzepatide (0.07 mg/kg QD), or

5) tirzepatide (0.07 mg/kg QD) and ALK7 surrogate siRNA 3 mg/kg weekly (N=10/group)

Co-treatment of tirzepatide and ALK7 siRNA at optimal dose levels had an additive effect on body weight and fat mass reductions

ALK7 siRNA ameliorated the significant loss of lean mass associated with tirzepatide

Lean mass

%BW change

-5

-10

-15

-20

-25

-30

-35

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

Saline

ALK7 siRNA (3 mg/kg) Tirzepatide (0.07 mg/kg QD)

Tirzepatide (0.07 mg/kg QD) + ALK7 siRNA

Fat mass (g)

25.94

10.57

11.70

5.83

Lean mass (g)

29.01

28.70

21.93

24.82

-40

Saline ALK7 Tirzepatide ALK7 +

(0.07 mg/kg) Tirzepatide

(0.07 mg/kg)

Saline ALK7 Tirzepatide ALK7 +

(0.07 mg/kg) Tirzepatide

(0.07 mg/kg)

TOXICOLOGICAL STUDY OF ARO-ALK7 IN HAN WISTAR RATS

6. ARO-ALK7 is well-tolerated subcutaneously in Han Wistar rats

ARO-ALK7 administered as a single dose of 30, 60, or 120 mg/kg (Day 15 necropsy), or repeat doses of 60 mg/kg on Day 1 and 29 (Day 43 necropsy)

Histopathological findings of vacuolated macrophage infiltrates at injection site/lymph nodes (≥60 mg/kg), liver Kupffer cell hypertrophy (≥30 mg/kg)

No adverse or dose-limiting findings were identified

ARO-ALK7

-2 0

2 4 8 12 16 20 24

Study Week

cALK7/cARL1

Relative Expression (Norm'd to Predose)

2.0

1.5

1.0

0.5

0.0

-2 0 2 4 6 8 10 12 14 16 18 20

Study Week

-80%

0.1 mg/kg

0.3 mg/kg

0.75 mg/kg

2.0

cALK7/cARL1

Relative Expression (Norm'd to Predose)

1.5

1.0

0.5

0.0

-2 0 2 4 6 8 10 12 14 16 18 20 22 24

Study Week

-80%

1.5 mg/kg

3 mg/kg

Chronic treatment of DIO mice with a surrogate of ARO-ALK7 suppressed body weight gain by 39%, reduced fat mass by 50%, and preserved lean mass compared to saline controls

ALK7 surrogate RNAi-treated DIO mice exhibited enhanced lipolysis and increased energy expenditure

Co-treatment of the ARO-ALK7 surrogate with tirzepatide in DIO mice enhanced body weight reduction and fat loss relative to tirzepatide

The dynamic range (0.1 - 0.75 mg/kg) of ARO-ALK7 was evaluated in cynomolgus monkeys (N=4/group)

A single dose of ARO-ALK7 resulted in a dose-dependent reduction of ALK7 mRNA expression

The duration of ARO-ALK7 was evaluated in cynomolgus monkeys (N=4/group)

A single 3 mg/kg ARO-ALK7 dose resulted in ~89% ALK7 mRNA silencing in adipose tissue after 1 month, and ~75% silencing for up to 12 weeks

monotherapy

In NHPs, a single subcutaneous dose of ARO-ALK7 resulted in a dose-dependent and durable reduction in ALK7 mRNA expression in subcutaneous fat

ARO-ALK7 was well tolerated in Han Wistar rats in non-GLP toxicological studies

Disclaimer

Arrowhead Pharmaceuticals Inc. published this content on May 12, 2025, and is solely responsible for the information contained herein. Distributed via Public Technologies (PUBT), unedited and unaltered, on May 12, 2025 at 20:02 UTC.