Arrowhead Pharmaceuticals has commenced a Phase I/IIa clinical trial (AROINHBE-1001, NCT06700538) evaluating ARO-INHBE, an investigational RNA interference (RNAi) therapeutic, for the treatment of obesity. The first patient has been dosed in this study, which aims to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of ARO-INHBE as both a monotherapy and in combination with tirzepatide.
Targeting INHBE for Improved Metabolic Health
ARO-INHBE is designed to reduce the hepatic expression of the INHBE gene, which encodes Activin E. Preclinical data suggest that lower levels of INHBE are associated with improved fat distribution and a reduced risk of metabolic diseases, including type 2 diabetes. This novel mechanism of action could potentially offer advantages over existing obesity therapies.
James Hamilton, chief of discovery and translational medicine at Arrowhead, stated, "ARO-INHBE is an important program for Arrowhead that complements our strategic focus on developing and commercializing important RNAi-based therapies for cardiometabolic diseases. Further, our preclinical studies have yielded promising results for this novel mechanism to reduce body weight and potentially preserve lean muscle mass resulting in improved body composition."
Trial Design and Objectives
The AROINHBE-1001 trial is a dose-escalating study that plans to enroll up to 78 adult volunteers with obesity. Part 1 of the study will evaluate single and multiple ascending doses of ARO-INHBE as a monotherapy. Part 2 will assess ARO-INHBE in combination with tirzepatide, a subcutaneously administered GLP-1/GIP receptor co-agonist. The primary objectives of the trial include assessing the safety and tolerability of ARO-INHBE. Secondary endpoints will evaluate the impact on body weight, fat mass, and other metabolic parameters.
RNAi Approach to Obesity Treatment
Arrowhead's ARO-ALK7 is another RNAi therapy targeting adipose tissues and is engineered to suppress the activin A receptor type 1C (ACVR1C) gene in fat cells, thereby reducing Activin receptor-like kinase 7 (ALK7) production. Arrowhead now has two clinical-stage RNAi-based candidates, ARO-ALK7 and ARO-INHBE, for the treatment of obesity. Both have a novel mechanism of action, with ARO-INHBE inhibiting a ligand and ARO-ALK7 inhibiting a receptor to intervene in a known pathway that signals the body to store fat in adipose tissue. Both targets are also supported by human genetics, where loss-of-function carriers have favourable body composition and metabolic characteristics compared to non-carriers.
Competitive Landscape
The obesity treatment market has seen significant activity, with the rise of GLP-1 inhibitors like Novo Nordisk's Wegovy (semaglutide) and Eli Lilly's Zepbound (tirzepatide). Arrowhead's approach with ARO-INHBE and ARO-ALK7 represents a novel strategy to address obesity by targeting specific genes involved in fat storage and metabolism.
