Late-breaking abstract: Attenuation of allergen-induced asthmatic responses by inhaled GATA-3 specific DNAzyme

Background The most prevalent phenotype of asthma is characterized by a TH2-driven eosinophil dominated inflammation. Therapeutic targeting of GATA-3, the master transcription factor of the TH2 pathway, may be beneficial. We evaluated the safety and efficacy of a novel DNAzyme specifically directed against GATA-3 mRNA (SB010). Methods In this randomized, double-blind, placebo-controlled, multicenter clinical trial, patients with allergic asthma with sputum eosinophilia exhibiting a biphasic early and late phase asthmatic response (EAR and LAR, respectively) following specific allergen provocation were assigned to receive 10 mg SB010 (N=21) or placebo (N=19) by inhalation once daily for 28 days. Allergen challenge was performed before and after treatment. Change in the area under the FEV1 curve (AUC) in LAR was the primary endpoint. Results SB010 attenuated the decline in mean FEV1 AUC by 34% compared with a 1% worsening in the placebo group (P=0.02) during LAR and by 11% compared with a 10% worsening in the placebo group during EAR (P=0.03). These effects were more pronounced in pre-specified subgroups of patients with blood eosinophils ≥ 4% (improvement LAR 41.7%, P=0.05; improvement EAR 28.3%, P=0.02) or FeNO ≥ 40 ppb. Lung function improvement was associated with changes in various TH2 pathway related biomarkers, including serum periostin, sputum eosinophils, eosinophilic cationic protein, and mast cell tryptase. No serious treatment emergent adverse events were reported. Conclusions SB010 treatment significantly attenuated both LAR and EAR following allergen provocation. Biomarker analysis revealed a strong effect on TH2 regulated inflammatory responses (Clinical Trials NCT 01743768).