Ioannis Psallidas1, Vibeke Backer2, Piotr Kuna3, Robert Palmér4, Sofia Necander5, Malin Aurell5, Katarina Korsback5, Ziad Taib6, Mahdi Hashemi6, Per Gustafson7, Sara Asimus4, Stephen Delaney8, Katerina Pardali9, Fanyi Jiang10, Joachim Almquist4, Sam Jackson11, Robert L Coffman11, David Keeling5, Tariq Sethi1. 1. Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom. 2. Center for Physical Activity Research, Rigshospitalet and Copenhagen University, Copenhagen, Denmark. 3. Department of Internal Medicine, Asthma and Allergy, Medical University of Łódź, Łódź, Poland. 4. Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences, R&D. 5. Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D. 6. Early Clinical Biostatistics and Statistical Innovation, Data Science & AI, BioPharmaceuticals R&D. 7. BioPharmaceuticals Medical. 8. Bioscience, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D. 9. Precision Medicine BioPharmaceuticals, R&D, and. 10. Translational Science and Experimental Medicine, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; and. 11. Dynavax Technologies, Berkeley, California.
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.
RCT Entities:
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.
Entities:
Keywords:
T-helper cell type 1 response; TLR9 activation; fractional exhaled nitric oxide; loss of asthma control; withdrawal study
Authors: David L Goldblatt; Gabriella Valverde Ha; Shradha Wali; Vikram V Kulkarni; Michael K Longmire; Ana M Jaramillo; Rosha P Chittuluru; Adrienne Fouts; Margarita Martinez-Moczygemba; Jonathan T Lei; David P Huston; Michael J Tuvim; Burton F Dickey; Scott E Evans Journal: Front Pharmacol Date: 2022-08-29 Impact factor: 5.988