A first-in-human trial has shown an inhaled RNA interference therapy can safely silence a key driver of lung inflammation for weeks at a time.
An inhaled gene-silencing therapy has produced deep and sustained reductions in a protein implicated in asthma and COPD, raising the prospect of a new approach to inflammatory lung disease.
Results from the phase 1/2a trial of the therapy known as ARO-RAGE, published in Nature Medicine, showed the small interfering RNA (siRNA) therapy was well tolerated and achieved substantial target knockdown in both healthy volunteers and people with mild-to-moderate asthma.
“Despite advances in asthma and COPD management, a substantial proportion of patients remain refractory to standard inhaled corticosteroids (ICSs) and bronchodilators (long-acting β2 agonists and long-acting muscarinic antagonists), necessitating novel therapeutic strategies,” the researchers wrote.
“Current biologics targeting T2 cytokines (for example, IL-5, IL-4Rα, and thymic stromal lymphopoietin) have demonstrated improved outcomes in subsets of patients, particularly those with markers of elevated T2 inflammation.
“However, many individuals – particularly those with neutrophilic or mixed inflammatory phenotypes – continue to experience exacerbations, progressive lung function decline and increased mortality, and are less responsive to current available biologics.
“This underscores the urgent need for therapies capable of targeting a broader range of inflammatory pathways simultaneously.”
The therapy is designed to silence expression of the receptor for advanced glycation end products (RAGE), which is highly expressed in the lung and helps amplify and sustain innate immune responses. It has been implicated in several pulmonary disorders, including asthma and COPD.
The randomised, double-blind, placebo-controlled study included 58 healthy volunteers and 19 people with asthma. Its primary endpoint was safety and tolerability, with pharmacokinetics a secondary endpoint and pharmacodynamics a more exploratory outcome.
In healthy volunteers, a single 184mg dose produced a mean 90.2% reduction in soluble RAGE (sRAGE) in bronchoalveolar lavage fluid at day 31 and a maximum mean 76.6% reduction in serum sRAGE at day 29.
The effect was also durable. After two 184mg doses, mean maximum serum sRAGE reduction reached 88.7% in healthy volunteers. In participants with asthma, two doses produced a mean maximum reduction of 76.2%, with the response broadly consistent with that seen in healthy volunteers.
The therapy was generally well tolerated, with headache and upper respiratory infection among the most commonly reported adverse events.
There were no clinically relevant changes in chest x-rays or evidence of worsening FEV1 or FVC among participants with asthma. Mild, transient reductions in DLCO of about 10% occurred at day 57 at the two highest doses but returned to baseline by day 113.
The therapy also appeared largely to stay where it was intended, the researchers said. Plasma concentrations were low, consistent with retention in the lung and limited systemic exposure.
They said the approach could be particularly interesting because RAGE was involved in both eosinophilic and neutrophilic inflammatory pathways. Current biologics have transformed treatment for some patients with T2-high asthma, but options remain more limited for people with T2-low, neutrophilic or mixed inflammation.
Earlier preclinical experiments reinforced that possibility. RAGE silencing reduced eosinophil and neutrophil recruitment in an allergic asthma model and attenuated inflammatory responses in models of COPD-emphysema and acute lung injury.
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The researchers said the results provided evidence supporting further investigation of ARO-RAGE and demonstrated that an epithelial-targeted siRNA could be delivered safely and directly to the lung with sustained target engagement and without obvious pulmonary toxicity.
“This study also generally supports the use of αvβ6 integrin ligand-targeted siRNA as a modality to silence targets expressed in the pulmonary alveolar epithelium,” they concluded.
“ARO-RAGE demonstrated robust efficacy across diverse preclinical models and excellent tolerability with substantial target engagement in nonhuman primates, healthy volunteers and patients with asthma.
“These promising translational findings strongly support further clinical development of ARO-RAGE as a novel therapeutic strategy to reduce inflammation, prevent tissue damage, and potentially slow disease progression in treatment-resistant asthma and COPD.”
