Arrowhead Seeks Regulatory Approval for Phase 1/2a ARO-INHBE Obesity Study

Arrowhead Pharmaceuticals, Inc., based in Pasadena, CA, has announced its application for regulatory clearance to begin a Phase 1/2a clinical trial for ARO-INHBE, an investigational RNA interference (RNAi) therapeutic aimed at treating obesity. The company also intends to seek regulatory approval by the end of 2024 for clinical trials of another obesity treatment candidate, ARO-ALK7.

Dr. James Hamilton, the Chief of Discovery and Translational Medicine at Arrowhead, stated that both ARO-INHBE and ARO-ALK7 target the same biological pathway that signals fat storage in adipose tissue. Promising preclinical results indicate that these therapies may reduce body and fat mass while preserving lean muscle, enhancing overall body composition. Dr. Hamilton mentioned that the initial Phase 1/2a study would evaluate ARO-INHBE's safety and efficacy in single and multiple doses, initially enrolling patients with obesity. The second part of the study would combine ARO-INHBE with tirzepatide, involving both diabetic and non-diabetic obese patients. He emphasized the potential of these novel therapies to revolutionize obesity treatment.

ARO-INHBE aims to suppress the hepatic expression of the INHBE gene and its protein product, Activin E. Research has shown that INHBE variants associated with loss-of-function in humans correlate with a lower risk of obesity and metabolic diseases like type 2 diabetes. Activin E is a ligand in a pathway that regulates energy balance in adipose tissue. By targeting this pathway, ARO-INHBE could potentially enhance lipolysis and reduce adipose hypertrophy, visceral fat, and insulin resistance.

The application to initiate the clinical trial has been submitted to the New Zealand Medicines and Medical Devices Safety Authority for review. Upon approval, Arrowhead plans to proceed with a Phase 1/2a dose-escalating study, named AROINHBE-1001. This study will assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of ARO-INHBE in up to 78 adult volunteers with obesity. The study's first part will evaluate single and multiple doses of ARO-INHBE monotherapy. The second part will study ARO-INHBE in combination with tirzepatide, a GLP-1/GIP receptor co-agonist approved for type 2 diabetes management in the United States and the European Union since 2022, and for weight management since 2023/2024.

Arrowhead Pharmaceuticals focuses on developing treatments for challenging diseases by silencing the genes responsible for them. Utilizing a broad range of RNA chemistries and effective delivery methods, Arrowhead's therapies activate the RNA interference mechanism to achieve significant, lasting reductions in target gene expression. RNA interference, or RNAi, is a natural cellular process that inhibits specific gene expression, subsequently affecting the production of particular proteins. Arrowhead’s RNAi-based therapeutics harness this pathway for gene silencing, aiming to address various intractable diseases.