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

Rationale: To examine the potential of TLR9 (Toll-like receptor 9) activation to modulate the type 2 immune response in asthma. Objectives: To evaluate efficacy and safety of AZD1419, an inhaled TLR9 agonist, in a phase 2a, randomized, double-blind trial. Methods: Adult patients with asthma with a history of elevated eosinophils (>250 cells/mu l) were randomized 1:1 to receive 13 onceweekly doses of inhaled AZD1419 (1, 4, or 8 mg; n= 40) or placebo (n = 41). Inhaled corticosteroids and long-acting f3 2 -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). Measurements and Main Results: 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 (FENO). LOC was predicted by an early rise in FENO in 63% of patients. Despite withdrawal of maintenance treatment, 24 patients completed the study without LOC; AZD1419 n = 11, placebo n = 13. Adverse events were balanced across groups, with no deaths or serious adverse events judged as causally related to AZD1419. Conclusions: 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 FENO is possible for patients with well-controlled asthma.

Automated summary

The study showed that although AZD1419 can reduce markers of type 2 inflammation in asthma, it did not improve asthma control; 63% of patients' LOC was predicted by an early rise in FENO; a novel accelerated step-down approach based on FENO may be applicable for patients with well-controlled asthma.