Arrowhead to advance two RNAi-based obesity candidates into clinical studies

Arrowhead Pharmaceuticals presented preclinical data and detailed its plans to advance two next generation RNAi-based candidates, ARO-INHBE and ARO-ALK7, into upcoming clinical studies for the treatment of obesity and metabolic diseases. In preclinical studies to date, these candidates demonstrated 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. Arrowhead plans to submit clinical trial applications with regulatory authorities for both programs by the end of 2024 with the goal of initiating clinical studies in volunteers with obesity in early 2025. ARO-INHBE is designed to reduce the hepatic expression of the INHBE gene and its secreted gene product, Activin E. ARO-ALK7 is designed to reduce the adipose expression of Activin receptor-like kinase 7. INHBE and ALK7 are both genetically validated targets with loss of function variants being associated with lower risk of obesity and metabolic diseases, such as type 2 diabetes. Both targets are involved in the same pathway that regulates energy homeostasis in adipose tissue, with Activin E acting as a circulating ligand and ALK7 as a receptor on adipocytes. Intervening in this pathway with ARO-INHBE and ARO-ALK7 is believed to result in increased lipolysis, and reductions in adipose hypertrophy and dysfunction, visceral adiposity, and insulin resistance.