Arrowhead presents data on candidates to treat obesity, metabolic diseases

Arrowhead (ARWR) announced presentation of preclinical data supporting the advancement of two clinical stage, RNAi-based investigational therapeutics being developed for the treatment of obesity and metabolic diseases. The two candidates, ARO-INHBE and ARO-ALK7, have the potential to reduce body weight and fat mass with a novel mechanism of action that may lead to improved preservation of lean muscle mass compared to currently approved obesity therapies. The presentation was included in the Oligo-Based Therapeutics: Clinical Advancements session at the RNA Leaders Europe Congress 2025 held March 4-6 in Basel, Switzerland. In a diet-induced obese 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. 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 December 2024 with initial data possible by year end 2025. The company anticipates dosing in the ARO-ALK7 study will begin in the second quarter of 2025 with initial data from the single-ascending dose portion of the study possible by year end 2025.