1626-P: Liver-Specific Silencing of INHBE with ARO-INHBE, an siRNA Therapeutic, for Metabolic Diseases

Introduction and Objective: Incretin-based therapies are evidently powerful and effective for obesity and cardiometabolic outcomes. However, the accompanying loss of significant lean body mass (LBM) and gastrointestinal adverse effects are of concern, and have inspired identification of novel modes of action for fat loss while preserving LBM. Loss-of-function INHBE variants are associated with a lower abdominal to gluteofemoral fat ratio, and protection against type 2 diabetes. Silencing INHBE expression represents a novel therapeutic approach for obesity and metabolic diseases. Here we describe a liver targeted siRNA therapeutic designed to silence INHBE expression.

Methods: siRNA conjugates targeting hepatic INHBE were designed. The pharmacodynamic properties of ARO-INHBE were evaluated in cynomolgus monkeys, and the pharmacological impact was assessed in DIO and db/db mice using a mouse surrogate of ARO-INHBE. Body weight, body composition, glucose homeostasis, and lipid metabolism were assessed during the studies.

Results: In cynomolgus monkeys, ARO-INHBE achieved deep knockdown of INHBE transcripts for a duration of at least 85 days with subcutaneous injections at 3 mpk on D1 and D29. In DIO and db/db mice, weekly dosing of the ARO-INHBE surrogate significantly suppressed body weight gain and decreased fat mass, but maintained lean mass and glucose homeostasis. Treatment with the surrogate of ARO-INHBE also improved the sensitivity of the DIO mice to catecholamine, indicated by the increased circulating ketone levels.

Conclusion: ARO-INHBE effectively silences hepatic INHBE mRNA. In the DIO mouse model, liver-specific silencing of INHBE mRNA caused the suppression of fat mass gain, but preservation of LBM. A clinical lead siRNA targeting INHBE has been selected.