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

Abstract

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/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 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).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.

• Authors: 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
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 203 Issue 3 Pg. 296-306 (02 01 2021) ISSN: 1535-4970 [Electronic] United States
• PMID: 32809843 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Asthmatic Agents
• Immunologic Factors
• Oligonucleotides
• TLR9 protein, human
• Toll-Like Receptor 9

Topics

• Administration, Inhalation
• Adult
• Aged
• Anti-Asthmatic Agents (administration & dosage, therapeutic use)
• Asthma (drug therapy, immunology)
• Double-Blind Method
• Female
• Humans
• Immunologic Factors (therapeutic use)
• Male
• Middle Aged
• Oligonucleotides (therapeutic use)
• Toll-Like Receptor 9 (agonists, drug effects, therapeutic use)
• Treatment Outcome