Arrowhead Pharmaceuticals Showcases Two Clinical-Stage RNAi-Based Candidates to Treat Obesity and Metabolic Diseases
- ARO-INHBE and ARO-ALK7 both target a known pathway that signals the body to store fat in adipose tissue with a novel mechanism of action that may better preserve lean muscle mass compared to currently approved obesity therapies
- Data highlight Arrowhead’s leadership in the use of RNA interference to potentially treat Obesity
“Arrowhead is leading the field in the discovery and development of potential new RNAi-based therapies for obesity and metabolic diseases. Our first two programs, ARO-INHBE and ARO-ALK7, both seek to intervene in a known biological pathway with strong support from human genetics studies and compelling preclinical results in mouse models of obesity where INHBE silencing in the liver and ALK7 silencing in adipose tissue led to dramatic reductions in fat mass without reductions in lean mass.” said
Select ARO-INHBE Preclinical Results:
In a diet-induced obese (DIO) mouse model, hepatic INHBE silencing with siRNA led to a 19% suppression in body weight gain relative to vehicle controls. Treated mice exhibited improved body composition with a 22% reduction of fat mass while preserving lean mass. Treated mice also demonstrated a trend to improved glycemic control. Hepatic INHBE silencing in DIO mice enhanced catecholamine sensitivity, increasing lipid mobilization and oxidation, which was not associated with liver steatosis. In fact, treated animals showed less liver fat accumulation relative to saline controls.
Select ARO-ALK7 Preclinical Results:
DIO mice treated with an ALK7 siRNA exhibit a 39% suppression in body weight gain relative to controls. Adipose ALK7 silencing reduced fat mass by 50% while preserving lean mass. Similar to INHBE silencing in hepatocytes, ALK7 silencing in adipocytes enhanced catecholamine sensitivity, increasing lipid mobilization and oxidation, which was not associated with liver steatosis. In fact, treated animals showed less liver fat accumulation relative to saline controls. In combination studies with tirzepatide, ALK7 siRNA enhanced the therapeutic benefits versus tirzepatide monotherapy, with additive effects on body weight and fat mass reduction while ameliorating the significant loss of lean mass associated with tirzepatide monotherapy.
Arrowhead believes it is the first company to initiate clinical studies against these two novel targets, INHBE and ALK7. INHBE, and the ligand it encodes Activin E, signals the ALK7 receptor on adipose tissue to store fat and suppress lipolysis. Intervening in this known biological pathway has the potential to improve adipose dysfunction in obesity by increasing lipolysis and reducing adipose hypertrophy and visceral adiposity. In addition, published human genetics studies suggest that loss-of-function variants of INHBE and/or ALK7 are associated with reduced abdominal fat and lower risk of coronary heart disease and type 2 diabetes.
Arrowhead is currently conducting Phase 1/2 clinical studies of ARO-INHBE and ARO-ALK7. Dosing in the ARO-INHBE study was initiated in
The presentation may be accessed on the Events and Presentations page in the Investors section of the Arrowhead website.
About ARO-INHBE
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.
About the AROINHBE-1001 Phase 1/2 Study
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
About ARO-ALK7
ARO-ALK7 is designed to silence adipocyte expression of the ACVR1C gene to reduce the 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. Treatment with investigational ARO-ALK7 has the potential to reduce visceral adiposity and improve lipid and glycemic parameters.
About the AROALK7-1001 Phase 1/2a Study
AROALK7-1001 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, a subcutaneously administered GLP-1/GIP receptor co-agonist that has been approved in
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