Trial reportNature medicine2026
Inhaled siRNA therapy targeting RAGE for pulmonary inflammation: a first-in-human randomized trial.
Trial report in Nature medicine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT05276570 (A Phase 1/2a Study Evaluating the Effects of ARO-RAGE Inhalation Solution in Healthy Subjects and Patients With Inflammatory Lung Disease), which is not on this map. Not yet cited in PubMed.
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The trial behind it
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A Phase 1/2a Study Evaluating the Effects of ARO-RAGE Inhalation Solution in Healthy Subjects and Patients With Inflammatory Lung Disease
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16 authors.
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Abstract
The receptor for advanced glycation end products (RAGE), a multiligand receptor that is abundantly expressed by lung alveolar type-1 cells, amplifies and sustains the innate immune response in a variety of pulmonary disorders, including asthma and chronic obstructive pulmonary disease. Here we developed ARO-RAGE, an inhaled, lung-epithelium-targeted siRNA directed against pulmonary RAGE mRNA. Preclinical data from rat models of asthma, chronic obstructive pulmonary disease and acute lung injury, as well as mouse models for assessment of inflammatory responses, demonstrated deep and durable silencing of RAGE, limiting pulmonary inflammation. In macaques, ARO-RAGE produced dose-dependent reductions in membrane-bound RAGE levels in lung tissue and soluble RAGE (sRAGE) levels in serum; moreover, bronchoalveolar lavage showed post-dose decreases in sRAGE levels, consistent with robust silencing of lung membrane-bound RAGE. We then tested ARO-RAGE in a phase 1/2a, randomized, double-blinded, placebo-controlled trial designed to assess safety and tolerability (primary endpoint), pharmacokinetics (secondary endpoint) and pharmacodynamics (exploratory endpoint). In healthy volunteers (total n = 58, male n = 14) and in patients with asthma (total n = 19, male n = 6), inhaled ARO-RAGE was safe and well tolerated. No clinically relevant changes in chest x-ray findings, pulmonary function tests or systemic markers of inflammation were observed in the two cohorts. Plasma levels of ARO-RAGE were low, consistent with drug retention in the lung and minimal systemic bioavailability. Prolonged dose-responsive decreases in serum and bronchoalveolar lavage sRAGE levels indicated effective pulmonary target engagement. Together, these results demonstrate safe pulmonary delivery and target engagement of an inhaled, epithelial-targeted therapeutic siRNA, and support continued clinical development of ARO-RAGE. ClinicalTrials.gov registration: NCT05276570 .
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