Pasadena, CA — January 6, 2026 — Leads & Copy — Arrowhead Pharmaceuticals Inc. announced interim results from two Phase 1/2a clinical trials of ARO-INHBE and ARO-ALK7, investigational RNA interference (RNAi) therapeutics being developed as potential obesity treatments.
Preliminary results with Arrowhead’s approach to treating obesity and metabolic diseases showed reductions in visceral fat, total fat, and liver fat. ARO-INHBE, combined with tirzepatide, a GLP-1/GIP receptor co-agonist, doubled weight loss and tripled reductions in visceral fat, total fat, and liver fat versus tirzepatide alone in obese patients with type 2 diabetes mellitus. The company expects to report additional results in 2026.
Carel le Roux, M.D., Ph.D., Chair in Chemical Pathology and Metabolic Medicine at University College Dublin School of Medicine, stated that new therapeutic approaches should focus on reducing visceral fat and combining therapies to achieve a low cardiovascular risk state and improve cardio-renal-metabolic outcomes.
Le Roux added that results for ARO-INHBE and ARO-ALK7 show reductions in visceral fat. Furthermore, ARO-INHBE in combination with tirzepatide almost doubled weight loss and improved multiple measures of body composition versus tirzepatide alone in patients with obesity and type 2 diabetes mellitus. He said this demonstrates therapeutic potential for RNAi-based targeting of the Activin E/ALK7 pathway directly in a patient population that typically loses less weight on therapy and experiences worse cardiovascular outcomes compared to non-diabetic patients.
The results represent the first demonstration in humans that the Activin E/ALK7 pathway, which regulates adipose fat storage, may potentially be harnessed to improve body composition and enhance weigh loss versus tirzepatide treatment alone in obese patients with type 2 diabetes mellitus.
James Hamilton, M.D., MBA, Chief Medical Officer and Head of R&D at Arrowhead, said that shortcomings around loss of lean mass, tolerability related to GI effects, reduced response in patients with diabetes, and disproportional fat mass gain after cessation of therapy remains a challenge for many patients.
Hamilton added that interim results from the Phase 1/2a studies of ARO-INHBE and ARO-ALK7 provide early evidence that targeting the Activin E/ALK7 pathway may address some of the limitations in current standard-of-care obesity treatments. The ARO-INHBE and ARO-ALK7 programs are important strategically for Arrowhead and demonstrate Arrowhead’s leadership in the design and development of RNAi-based therapies.
A single dose of ARO-INHBE in adult volunteers with obesity achieved a dose-dependent reduction in serum Activin E with a mean maximum reduction of -85% after a single 400 mg dose and a maximum observed reduction of -94%.
Single-dose ARO-INHBE monotherapy at week 16 led to:
- Mean visceral fat reduction of -9.9%
- Mean liver fat relative reduction of -38%
- Increased total lean tissue of 3.6%
Two doses of ARO-INHBE monotherapy at Week 24 achieved:
- Mean visceral fat reduction of -15.6%, adjusted for placebo.
Two doses of ARO-INHBE (400 mg) in combination with tirzepatide achieved approximately two-fold weight loss at week 16 and an approximately three-fold reduction in fat, based on the week 12 MRI, versus tirzepatide alone in these patients. Results include the following, measured by mean percent change from baseline:
| Tirzepatide + Placebo | ARO-INHBE (400 mg) Tirzepatide Combination | |
|---|---|---|
| Weight Loss (week 16 weight) | -4.8 % (n=5) | -9.4% (n=4) |
| Visceral Fat (week 12 MRI) | -7.4% (n=5) | -23.2% (n=3) |
| Total Fat (week 12 MRI) | -5.3% (n=5) | -15.4% (n=3) |
| Liver Fat (relative reduction on (week 12 MRI) | -20% (n=5) | -76.7% (n=3) |
ARO-INHBE has been generally well tolerated to date as monotherapy and in combination with tirzepatide in participants with obesity with and without type 2 diabetes. Most treatment emergent adverse events (TEAE) were mild in severity. No TEAEs led to study or study drug discontinuation. Injection site reactions were generally mild and self-limited. One SAE of “limb abscess” was reported, managed with bedside drainage, and assessed as unrelated to study treatment by both sponsor and site investigator. Frequency of gastrointestinal (GI) adverse events was similar in combination and tirzepatide monotherapy groups. There were no clinically significant adverse laboratory trends including liver enzymes, glycemic indices, or lipid parameters.
ARO-ALK7 achieved dose-dependent reductions in adipose ALK7 mRNA with a mean reduction of -88% at the 200 mg dose at week 8 with a maximum reduction of -94% (n = 4).
A single dose of ARO-ALK7 led to rapid dose-dependent reductions in mean visceral fat with a -14.1% reduction, adjusted for placebo, already observed at Week 8.
ARO-ALK7 has been generally well tolerated to date as monotherapy in participants with obesity. No clinically significant adverse laboratory trends, including in liver enzymes and glycemic parameters, were identified. Most TEAEs were mild in severity. No TEAEs led to study or study drug discontinuation. No SAEs were reported.
The company is hosting a virtual webinar today, January 6, 2026, at 11:30 am EST featuring Carel le Roux M.D., Ph.D., Chair in Chemical Pathology and Metabolic Medicine at University College Dublin School of Medicine, who will join members of the Arrowhead management team to discuss the interim results of the Company’s Phase 1/2a studies of ARO-INHBE and ARO-ALK7. To register for the event, please visit: https://lifescievents.com/event/sa2ymsnv7/.
The live event and an archived webcast may also be accessed on the Events and Presentations page on the Investors section of the Arrowhead website.
ARO-INHBE is designed to reduce the hepatic expression of the INHBE gene and its secreted gene product, Activin E. INHBE is a promising genetically validated target in which loss-of-function INHBE variants in humans are associated with improved fat distribution and lower risk of metabolic diseases, such as type 2 diabetes. Activin E acts as a ligand in a pathway that regulates energy homeostasis in adipose tissue. Inhibiting this pathway with investigational ARO-INHBE treatment has the potential to increase lipolysis, and reduce adipose hypertrophy and dysfunction, visceral adiposity, and insulin resistance.
AROINHBE-1001 (NCT06700538) is a Phase 1/2a dose-escalating study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ARO-INHBE in up to 78 adult volunteers with obesity. Part 1 of the study is designed to assess single and multiple doses of ARO-INHBE monotherapy, and Part 2 of the study is designed to assess ARO-INHBE in combination with tirzepatide, a subcutaneously administered GLP-1/GIP receptor co-agonist that has been approved in the United States and the European Union for management of type 2 diabetes mellitus since 2022 and weight management since 2023/2024 respectively.
ARO-ALK7 is designed to silence adipocyte expression of the ACVR1C gene to reduce production of Activin receptor-like kinase 7 (ALK7), which acts as a receptor in a pathway that regulates energy homeostasis in adipose tissue. In large genetic datasets, reduced ACVR1C expression has been associated with healthier adipose distribution and reduced risk of obesity-related metabolic complications. In preclinical animal studies, ALK7 silencing in adipose tissue led to reduced body weight and fat mass with preservation of lean muscle. Treatment with investigational ARO-ALK7 has the potential to reduce visceral adiposity and improve lipid and glycemic parameters.
AROALK7-1001 (NCT06937203) is a Phase 1/2a first-in-human dose-escalating study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ARO-ALK7 in up to 90 adult volunteers with obesity. Part 1 of the study is designed to assess single and multiple doses of ARO-ALK7 monotherapy, and Part 2 of the study is designed to assess ARO-ALK7 in combination with tirzepatide.
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Source: Arrowhead Pharmaceuticals
