A Phase 2a, Double-Blind, Placebo-controlled Randomized Trial of Inhaled TLR9 Agonist AZD1419 in Asthma

Abstract

<b>Rationale:</b> To examine the potential of TLR9 (Toll-like receptor 9) activation to modulate the type 2 immune response in asthma.<b>Objectives:</b> To evaluate efficacy and safety of AZD1419, an inhaled TLR9 agonist, in a phase 2a, randomized, double-blind trial.<b>Methods:</b> Adult patients with asthma with a history of elevated eosinophils (>250 cells/μl) were randomized 1:1 to receive 13 once-weekly doses of inhaled AZD1419 (1, 4, or 8 mg; <i>n</i> = 40) or placebo (<i>n</i> = 41). Inhaled corticosteroids and long-acting β₂-agonist were tapered down and then discontinued. The last four doses of AZD1419 were given without maintenance medication, followed by a 40-week observation period. Primary endpoint was time to loss of asthma control (LOC).<b>Measurements and Main Results:</b> AZD1419 induced a T-helper cell type 1-type IFN response with a sustained reduction in markers of type 2 inflammation. However, there were no statistically significant differences between AZD1419 and placebo for time to LOC, proportion of patients with LOC, changes in Asthma Control Questionnaire-five-item version, exacerbations, reliever use, FEV₁, peak expiratory flow, or fractional exhaled nitric oxide (Fe_NO). LOC was predicted by an early rise in Fe_NO in 63% of patients. Despite withdrawal of maintenance treatment, 24 patients completed the study without LOC; AZD1419 <i>n</i> = 11, placebo <i>n</i> = 13. Adverse events were balanced across groups, with no deaths or serious adverse events judged as causally related to AZD1419.<b>Conclusions:</b> AZD1419 was safe and well tolerated but did not lead to improved asthma control, despite reducing markers of type 2 inflammation. Results suggest that a novel accelerated step-down approach based on Fe_NO is possible for patients with well-controlled asthma.