Arrowhead Pharmaceuticals : ECO 2026 LBP4078 Kerr Activin E Poster 6May2026 FINAL

Published: 2026-05-14 11:16:10 ET ARWR

Published on 05/14/2026 at 11:16 am EDT

1New Zealand Clinical Research, Christchurch, New Zealand; 2Division of Medicine, Middlemore Hospital, Te Whatu Ora Counties Manakau, Auckland, New Zealand; 3Aotearoa Clinical Trials, Auckland, New Zealand; 4Arrowhead Pharmaceuticals, Pasadena, California, United States; 5Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

P O ST E R

Incretin-based therapies promote weight loss and improve metabolic outcomes, but dose-dependent gastrointestinal adverse events, lean mass loss, and attenuated efficacy in individuals with diabetes highlight the need for therapies with novel mechanisms of action1,2

The Inhibin subunit beta E (INHBE) gene is primarily expressed in hepatocytes, where it encodes for Activin E (dimeric INHBE protein), a hepatokine that is secreted in the blood and believed to promote fat storage in adipocytes via the ALK7 receptor3

Predicted loss-of-function variants in INHBE are associated with a favorable metabolic profile and reduced cardiometabolic risk, including lower risk of Type 2 diabetes mellitus (T2DM)3,4

ARO-INHBE is an investigational small interfering RNA (siRNA) designed to silence hepatic INHBE mRNA expression (Figure 1) and may represent a therapeutic strategy for targeting obesity and adipose dysfunction5

ARO-INHBE

Excess caloric intake

Activin E production inhibited

ALK7

INHBE gene silenced

Hepatocyte

Adipocyte

Y Lipolysis

Y Circulating NEFA

Adipose hypertrophy & dysfunction

Visceral adiposity

Insulin resistance

Figure 1. Mechanism of Action

Preclinical studies evaluated levels of circulating Activin E in non-human primates (NHPs) with and without T2DM

ARO-INHBE-1001 is an ongoing Ph1/2a study evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of subcutaneously administered ARO-INHBE:

Part 1A and Part 1B enrolled adult participants with obesity (BMI: 30-50 kg/m2) who received single or multiple ascending doses of ARO-INHBE

Part 2 enrolled adult participants with obesity, with T2DM (HbA1c: 6.7-9.5%) or without T2DM (HbA1c <6.5%), who were randomized to receive multiple doses of ARO-INHBE concurrently with low-dose tirzepatide or tirzepatide alone

Associations between Activin E levels and Clinical Characteristics at Baseline were evaluated using Pearson Correlation coefficient values (r)

Baseline was defined as the last measurement obtained before the first dose of study drug; where not available or measurement error was likely, the

Figure 2. Study Design

Cohort 1a

(50 mg ARO-INHBE) (n=6)

Part 1B MAD (8 Active : 4 Placebo)

Part 2 (8 Active : 4 Placebo)

Cohort 2a

(100 mg ARO-INHBE) (n=6)

Cohort 2b

Cohort 2c

Cohort 2b

(100 mg ARO-INHBE) (n=12)

Cohort 2c

(100 mg ARO-INHBE + TZP 5mg vs.

TZP 5 mg alone) (n=12)

Cohort 3a

(200 mg ARO-INHBE) (n=6)

Cohort 3b

Cohort 3c

Cohort 3d

Cohort 4a

(400 mg ARO-INHBE) (n=6)

Cohort 3b

(200 mg ARO-INHBE) (n=12)

Cohort 3c

(200 mg ARO-INHBE + TZP 5mg vs.

TZP 5 mg alone) (n=12)

Cohort 3d

(200 mg ARO-INHBE + TZP 5mg vs.

TZP 5mg alone) [T2DM] (n=12)

Cohort 4b

Cohort 4c

Cohort 4d

Cohort 4b

(400 mg ARO-INHBE) (n=12)

Cohort 4c

(400 mg ARO-INHBE + TZP 5mg vs.

TZP 5 mg alone) (n=12)

Cohort 4d

(400 mg ARO-INHBE + TZP 5mg vs.

TZP 5mg alone) [T2DM] (n=12)

Part 1A SAD (4 Active : 2 Placebo)

preceding (Screening) value was used

MAD, multiple ascending dose; SAD, single ascending dose; T2DM, type 2 diabetes mellitus; TZP, tirzepatide

Mean weight (103.7 vs 104.2 kg) and BMI (36.8 vs 37.0 kg/m2) were similar between groups (Table 1)

Figure 4. Activin E Levels Correlate with Insulin Resistance and Anthropometric Measures in AROINHBE-1001 Participants with Diabetes

Participants with obesity and T2DM had higher mean

HOMA-IR

Insulin

BMI Waist Circumference Waist:Height

liver fat content, visceral fat content, HbA1c, and Activin E levels compared to participants with obesity alone

Table 1. Baseline Demographic and Clinical Characteristics of AROINHBE-1001 Participants

1200

Activin E (pg/mL)

900

600

300

r=0.65 r=0.40

1200

r=0.74 r=0.37

900

600

300

1200

r=0.73 r=0.12

900

600

300

1200

r=0.46 r=0.09

900

600

300

1200

r=0.49 r=0.13

900

600

300

Participants with Obesity and T2DM (N=21)

Participants with Obesity (N=96)

Age, mean (SD), year

51.3 (7.7)

43.5 (11.4)

Sex, Female, n (%)

11 (52.4)

66 (68.8)

Race, n (%)

White

12 (57.1)

62 (64.6)

Native Hawaiian or Pacific Islander

5 (23.8)

23 (24.0)

Asian

2 (9.5)

12 (12.5)

Other

3 (14.3)

8 (8.3)

Black or African American

0 (0)

2 (2.1)

Weight, mean (SD), kg

103.7 (17.8)

104.2 (15.6)

BMI, mean (SD), kg/m2

36.8 (6.1)

37.0 (4.8)

Liver fat content, mean (SD), %

17.7 (9.6)

6.9 (5.5)

Visceral adipose tissue, mean (SD), L

6.8 (2.6)

4.7 (1.8)

HbA1c, mean (SD), %

7.4 (0.7)

5.4 (0.4)

Activin E, mean (SD), pg/mL

661.6 (234.1)

474.4 (171.0)

0 5 10 15 20 25

0 20 40 60

25 30 35 40 45 50 55

80 100 120 140 160 180

0.6 0.8 1.0 1.2

HOMA-IR (%)

Insulin (uIU/mL)

BMI (kg/m2) Waist Circumference (cm)

Waist:Height

SD, standard deviation; BMI, body mass index; T2DM, type 2 diabetes mellitus. Note: Patient may report more than one race; percentages may total over 100%.

Figure 3. Serum Activin E levels Are Elevated in Non-Human Primates with Diabetes and AROINHBE-1001 Study Participants

BMI, body mass index; HOMA-IR, homeostatic model assessment for insulin resistance

In ARO-INHBE-1001, baseline serum Activin E levels were observed to be correlated with insulin resistance (assessed with HOMA-IR) and insulin, irrespective of T2DM status

Baseline serum Activin E levels were more strongly correlated with anthropometric measures (BMI, waist circumference, and weight:height ratio) in participants with obesity and T2DM than participants with obesity alone

CONCLUSIONS

Activin E levels are elevated in T2DM and

associated with obesity, insulin resistance, and hepatic steatosis

These findings support dysregulation of the INHBE/Activin E pathway as a feature of the metabolic syndrome and provide a mechanistic rationale for targeting INHBE with ARO-INHBE in people with obesity and insulin resistance

Directly targeting adipose fat storage via hepatic Activin E may complement existing incretin-based approaches for weight management

The AROINHBE-1001 study is ongoing

Figure 5. Activin E Levels Correlate with Hepatic Steatosis

p < 0.0001

Mean ± SD Activin E (pg/mL)

1500

1000

Mean ± SD Activin E (pM)

250

200

150

100

Serum Activin E Levels in NHPs

Serum Activin E Levels in 1001 Study Participants

p = 0.0019

p=0.0055

Mean ± SD Activin E (pg/mL)

1500

1000

500

LFC <5% (No steatosis) LFC ≥8% (Steatosis)

n=50 n=48

No T2DM T2DM

n=9 n=8

500

No T2DM T2DM

n=96 n=21

LFC, liver fat content as determined by magnetic resonance imaging-proton density fat fraction

In ARO-INHBE-1001, baseline mean ± SD Activin E levels were significantly higher in individuals with clinically significant hepatic steatosis (599.5 ± 202.5 pg/mL) versus those without steatosis (421.2 ± 170.0 pg/mL)

In NHPs with T2DM, mean ± SD Activin E levels were

113.3 ± 51.1 pM (mean ± SD HbA1c of 9.0 ± 2.3%)

compared to 53.7 ± 17.4 pM in NHPs without T2DM (p=0.0055) (Figure 3)

Similarly, in participants with obesity and T2DM in AROINHBE-1001, baseline mean ± SD Activin E levels were 661.6 ± 234.1 vs 474.4 ± 171.0 pg/mL in participants with obesity alone (p=0.0019) (Figure 3)

A C K N O W L E D G E M E N T S

The authors thank the study participants, investigators, and staff. This study was sponsored by Arrowhead Pharmaceuticals, Inc., Pasadena, California. Arrowhead and the authors would like to thank Heather Hartley-Thorne of Sephirus Communications Inc. for graphical support and poster design. Michelle Po and Nathalie Kertesz of Arrowhead contributed to the writing and review.

D I S C L O S U R E S

R Murphy reports speaking honoraria from Lilly, Novo Nordisk, Boehringer Ingelheim; advisory board input to Abbot Diabetes Care, Dexcom, Lilly; and consultancy for NZ Clinical Trials. G Shekhtman, M Ngai, E Garcia-Medel, B Tomasini-Johansson, R Fu, ZM Ding, and J Hamilton are current employees of Arrowhead Pharmaceuticals.

R E F E R E N C E S

Jastreboff AM, et al. N Engl J Med. 2022;387(3):205-216.

Garvey WJ, et al. Lancet. 2023;402(10402):613-626. 3.

Deaton AM, et al. Nat Commun. 2022;13(1):4319. 4. Akbari

P, et al. Nat Commun. 2022;13(1):4844. 5. Ngai M, et al.

Diabetes. 2024;73 (Suppl 1):1626-P.

Download a copy of this poster at: https://www.arrowheadmedicalaffairs.com/ ECO2026/LBP4.078

Disclaimer

Arrowhead Pharmaceuticals Inc. published this content on May 14, 2026, and is solely responsible for the information contained herein. Distributed via Public Technologies (PUBT), unedited and unaltered, on May 14, 2026 at 15:15 UTC.