Late Breaking Abstract - A phase 1 study of subcutaneous administration of ARO-RAGE

<bold>Background:</bold> The receptor for advanced glycation end-products (RAGE) regulates type-2 and non-type 2 airway inflammatory pathways contributing to asthma. ARO-RAGE is an RNA-interference (RNAi)-based therapeutic designed to silence pulmonary RAGE expression. Inhalational delivery of ARO-RAGE results in pulmonary silencing of RAGE. <bold>Objective:</bold> ARORAGE-1002 (<ext-link>NCT05533294</ext-link>) assessed the safety, pharmacokinetics (PK), and pharmacodynamic effects of subcutaneously (SC) administered ARO-RAGE in healthy subjects. <bold>Methods:</bold> ARORAGE-1002 is a randomized, double-blind, placebo-controlled, phase 1 study. Subjects were randomized to receive ARO-RAGE or placebo (PBO) by SC injection as either single dose or multiple doses (2 doses at a 2-week interval) at ascending dose levels from 175 mg to 700 mg. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Plasma PK and changes in soluble RAGE (sRAGE) protein in serum and bronchoalveolar lavage fluid (BALF) were also measured. <bold>Results:</bold> 43 subjects were randomized to ARO-RAGE (n=31) or PBO (n=12). No serious TEAEs and no TEAEs leading to drug or study discontinuation were observed. Plasma exposure to ARO-RAGE was dose-dependent and consistent with SC administration with no evidence of systemic accumulation when dosed every 2 weeks. Serum sRAGE protein decreased in a dose-responsive manner, by up to 37% ± 8% (mean ± SD) after 2 doses of ARO-RAGE 700 mg. BALF sRAGE was maximally decreased by 62% ± 6% after 2 doses of ARO-RAGE 350 mg. Minimal sRAGE changes were observed following PBO. <bold>Conclusions:</bold> SC administration of ARO-RAGE was well tolerated. Pulmonary silencing of RAGE expression was achieved via SC delivery of a novel RNAi therapeutic.