Background: The receptor for advanced glycation end-products (RAGE) is an upstream regulator of both type-2 (T2) and non-T2 inflammatory cascades in the asthmatic airway. ARO-RAGE is an RNA-interference (RNAi) based therapeutic designed to silence pulmonary RAGE expression.

Objective: This interim analysis assessed the safety and pharmacodynamic effect of ARO-RAGE in healthy volunteers from the phase 1/2a ARORAGE-1001 study (NCT05276570).

Methods: ARORAGE-1001 is an ongoing, randomized, double-blind, placebo-controlled, phase 1/2a study. Healthy volunteers were randomized to receive inhaled ARO-RAGE or placebo as a single dose or multiple doses (2 doses at a 4-week interval) at ascending dose levels. The primary endpoint was the incidence of treatment-emergent adverse events (TEAEs). Target engagement was assessed via measurement of soluble RAGE (sRAGE) protein in serum and bronchoalveolar lavage fluid (BALF).

Results: Among 64 randomized subjects (n= 46 ARO-RAGE; n= 18 placebo), there have been no serious TEAEs and no TEAEs leading to study or drug discontinuation. At 4 weeks following 1 dose of 184 mg ARO-RAGE, BALF sRAGE decreased by 90% ± 4% (mean ± SD) and serum sRAGE decreased by 76% ± 9%, with minimal changes (0% ± 33% and -5% ± 16%, respectively) in placebo. At 6 weeks following 2 doses of 92 mg ARO-RAGE, serum sRAGE decreased by 76% ± 9%, while increasing by 6% ± 18% in placebo.

Conclusion: In healthy volunteers, ARO-RAGE has been safe and well tolerated, and resulted in pulmonary silencing of RAGE expression.  Further Phase 1 data from healthy volunteers and Phase 2a data from asthma patients are pending from the ongoing trial.