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

RATIONALE: To examine the potential of TLR9 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 asthma patients 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; n=40) or placebo (n=41). Inhaled corticosteroids (ICS) and long-acting β2-agonist (LABA) were tapered down and then discontinued. The last 4 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 Th1-type interferon 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 ACQ-5, exacerbations, reliever use, FEV1, PEF or 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 (AEs) were balanced across groups, with no deaths or serious AEs 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 well controlled asthma patients. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT02898662.