Arrowhead Highlights Clinical-Stage RNAi Therapies for Obesity and Metabolic Diseases
Arrowhead Pharmaceuticals, Inc. (NASDAQ: ARWR) recently showcased promising preclinical data supporting the advancement of two first-in-class, RNA interference (RNAi)-based investigational therapeutics, ARO-INHBE and ARO-ALK7, for the treatment of obesity and metabolic diseases. These novel candidates have demonstrated potential to reduce body weight and fat mass while preserving lean muscle mass, distinguishing them from currently approved obesity therapies. The findings were presented in a session titled “Targeting Obesity with RNAi-based Therapies” at the RNA Leaders Europe Congress 2025, held from March 4-6 in Basel, Switzerland.
James Hamilton, M.D., MBA, Chief Medical Officer and Head of R&D at Arrowhead, emphasized the company’s leadership in RNAi-based obesity therapies, stating, “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. INHBE silencing in the liver and ALK7 silencing in adipose tissue led to dramatic reductions in fat mass without reductions in lean mass.” He further announced that Phase 1/2 clinical trials would evaluate single- and multiple-ascending doses of ARO-INHBE and ARO-ALK7 as monotherapy and in combination with tirzepatide, a GLP-1/GIP receptor co-agonist.
ARO-INHBE Preclinical Findings:
Preclinical studies of ARO-INHBE in a diet-induced obese (DIO) mouse model demonstrated significant efficacy:
- Body Weight Management: INHBE silencing led to a 19% reduction in body weight gain compared to vehicle-treated controls.
- Fat Mass Reduction: Treated mice exhibited a 22% decrease in fat mass while preserving lean muscle mass.
- Glycemic Control: A trend toward improved glycemic control was observed, indicating a potential benefit in metabolic health.
- Liver Health: Unlike some obesity treatments associated with liver steatosis, INHBE silencing was found to enhance lipid mobilization and oxidation while reducing liver fat accumulation relative to saline-treated controls.
ARO-ALK7 Preclinical Findings:
- Significant Weight Suppression: Mice treated with ALK7-targeting siRNA exhibited a 39% suppression in body weight gain compared to controls.
- Fat Mass Reduction: ALK7 silencing led to a remarkable 50% reduction in fat mass while maintaining lean mass.
- Enhanced Lipid Mobilization: Increased sensitivity to catecholamines facilitated improved lipid oxidation without adverse liver effects.
- Synergistic Effects with Tirzepatide: When combined with tirzepatide, ARO-ALK7 demonstrated additive effects on weight and fat loss while mitigating the lean mass loss often observed with tirzepatide monotherapy.
The Novel Mechanism of Action:
Arrowhead is pioneering the clinical development of RNAi-based therapeutics targeting INHBE and ALK7. The INHBE gene encodes Activin E, which interacts with the ALK7 receptor on adipose tissue to regulate fat storage and suppress lipolysis. By silencing INHBE in hepatocytes and ALK7 in adipocytes, Arrowhead aims to enhance lipid metabolism and reduce visceral adiposity. This mechanism is further supported by genetic studies linking loss-of-function variants of INHBE and ALK7 to lower abdominal fat, decreased risk of coronary heart disease, and improved metabolic health.
Clinical Development Progress:
Arrowhead has initiated Phase 1/2 clinical studies for both candidates:
- ARO-INHBE: The first dosing began in December 2024, with initial data expected by the end of 2025.
- ARO-ALK7: Dosing is anticipated to commence in the second quarter of 2025, with early results from the single-ascending dose cohort also expected by year-end.
These studies will assess the safety, pharmacokinetics, and efficacy of single- and multiple-ascending doses, both as standalone therapies and in combination with tirzepatide, to determine their potential in reshaping obesity treatment paradigms.
Arrowhead’s presentation at the RNA Leaders Europe Congress underscores its commitment to developing innovative, RNAi-based solutions for obesity and metabolic disorders. The company’s pioneering work in targeting INHBE and ALK7 marks a significant step forward in the quest for safer, more effective weight-loss therapies.
For further details, the full presentation can be accessed on the Arrowhead Pharmaceuticals website under the Investors section.
