Unlocking the potential of RNAi therapies: Revolutionising treatment in the inflammatory lung disease landscape
Asthma is characterised by inflammation of the bronchial tubes and increased mucus production. Studies have shown that increased expression of the Receptor for Advanced Glycation End-products, RAGE, is associated with increased inflammatory signalling pathways in asthma. Accordingly, novel treatments are being designed to target this inflammatory pathway. Arrowhead Pharmaceuticals has aimed to target this pathway with their new inhaled RNAi therapy ARO-RAGE. The objective is to diminish the level of RAGE protein expression on pulmonary epithelial cells, thereby mitigating RAGE-associated inflammatory pathways and potentially resulting in a reduction in exacerbation occurrence and enhanced airflow.
On day 3 of ERS 2023, Arrowhead Pharmaceuticals revealed its late-breaking abstract including new data from its ongoing Phase 1/2a ARORAGE-1001 trial, a randomised, double-blind, placebo-controlled study evaluating ARO-RAGE, in adult healthy volunteers and asthma patients. Interim results from this study showed a 90% decrease at day 31 in bronchoalveolar lavage fluid (BALF) serum RAGE protein in the highest 184mg single dose cohort, with an ~80% decrease in serum sRAGE. Reduction of serum sRAGE was dose dependent and similar in healthy volunteers and asthma patients at the 44mg dose, however, the lower 10mg and 20mg dose groups did not show a decrease in serum sRAGE. Importantly, ARO-RAGE’s safety and tolerability profile revealed no serious AEs at any dose levels and no instances of any TEAEs leading to discontinuation or withdrawal; the single inhaled high-dose was overall well tolerated and demonstrated a significant level of target gene knockdown with a duration of effect that could support longer dosing intervals of 2 months or more.
Follow up multiple-ascending dose data (MAD) from Healthy Volunteers is expected by YE 2023 and should provide a clearer picture of the depth and durability of ARO-RAGE’s efficacy in this cohort, though full MAD data from all three asthma cohorts, which is expected in H1 2024, will be the key to determining the drug’s therapeutic window and which dose could be carried forward into larger studies. Arrowhead plans to initiate a Phase 2b study in an estimated 500 severe adult asthmatic patients stratified for blood eosinophil levels to measure exacerbation rate, FEV1, and QoL.
Should Arrowhead’s ARO-RAGE prove its efficacy in forthcoming trials, it could herald a paradigm-shifting breakthrough in the treatment of asthma. Currently, there are no RNAi therapies in the emerging drug pipeline for asthma that target the reduction of the RAGE protein expression in pulmonary epithelial cells. Therefore, if granted approval, this treatment holds the potential to secure a substantial portion of the asthma market and various other inflammatory lung diseases.
