To examine the potential of TLR9 activation to modulate the Type-2 immune response in asthma.
To evaluate efficacy and safety of AZD1419, an inhaled TLR9 agonist, in a phase 2a, randomized, double-blind trial.
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).
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.
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.
About The Expert
Ioannis Psallidas
Vibeke Backer
Piotr Kuna
Robert Palmér
Sofia Necander
Malin Aurell
Katarina Korsback
Ziad Taib
Mahdi Hashemi
Per Gustafson
Sara Asimus
Stephen Delaney
Katerina Pardali
Fanyi Jiang
Joachim Almquist
Sam Jackson
Robert L Coffman
David Keeling
Tariq Sethi
References
PubMed