ArticleBMJ open respiratory research2016
Tolerability in man following inhalation dosing of the selective TLR7 agonist, AZD8848.
Article in BMJ open respiratory research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to 2 registered trials, which are not on this map. Cited by 10 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Double-blind, Placebo-controlled, Randomised Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Ascending Inhaled Doses of AZD8848 in Healthy Subjects
A Phase 1, Single Centre, Double-blind, Randomised, Placebo-controlled, Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics After Administration of Multiple Ascending (MAD) Once Weekly Inhaled Doses of AZD8848 in Healthy Subjects
Who cites it
10 citing papers in PubMed, 21 citations in OpenAlex.
- Lung immune challenge study protocol: controlled exposure to inhaled resiquimod (R848) to study mechanisms of inflammation.Immunotherapy advances · 2025Article
- Evaluation of intranasal TLR2/6 agonist INNA-051: safety, tolerability and proof of pharmacology.ERJ open research · 2024Article
- Bacterial vesicles block viral replication in macrophages via TLR4-TRIF-axis.Cell communication and signaling : CCS · 2023Article
- TLR2-mediated activation of innate responses in the upper airways confers antiviral protection of the lungs.JCI insight · 2021Article
- Advancing Adjuvants forFrontiers in immunology · 2021Review
- EAACI Allergen Immunotherapy User's Guide.Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology · 2020Review
- Pulmonary Metabolism of Substrates for Key Drug-Metabolizing Enzymes by Human Alveolar Type II Cells, Human and Rat Lung Microsomes, and the Isolated Perfused Rat Lung Model.Pharmaceutics · 2020Article
- Toll-Like Receptor Agonists as Adjuvants for Allergen Immunotherapy.Frontiers in immunology · 2020Review
- TLR9-Activating CpG-B ODN but Not TLR7 Agonists Triggers Antibody Formation to Factor IX in Muscle Gene Transfer.Human gene therapy methods · 2019Article
- Strategies for designing synthetic immune agonists.Immunology · 2016Review
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundMany patients with asthma have a T-helper type 2 (Th2) driven inflammation of the lung, whereas toll-like receptor 7 (TLR7) agonists, by inducing type I interferons, inhibit Th2 responses. In man, oral or parenteral TLR7 agonists can induce influenza-like symptoms through systemic induction of type I interferons. Design of a TLR7 agonist that is only active in the lung could reduce the risk of side effects and offer a new means for treating asthma. We developed a TLR7 agonist antedrug, AZD8848, to determine its local and systemic effects in preclinical models and man.
methodsIn vitro cellular potencies for the TLR7 antedrug agonist, AZD8848, were determined along with pharmacokinetics and efficacy in a rat allergy model. Sputum and blood biomarkers were measured in single ascending and multiple ascending dose clinical studies following inhalation delivery of AZD8848 and tolerability assessed.
resultsAZD8848 was potent in cellular assays and pharmacokinetics confirmed lack of systemic exposure to AZD8848. Weekly lung dosing in an animal model showed efficacy 26 days beyond the final dose. In healthy volunteers, AZD8848 was initially well tolerated with target engagement being demonstrated by induction of CXCL10 in sputum. A second inhaled dose, given 1 week later, amplified the systemic interferon signal in more than half the participants and resulted in significant influenza-like symptoms.
conclusionsThe antedrug design restricted the direct actions of AZD8848 to the lung. However, the type I interferon induced locally by TLR7 spilled over systemically, limiting the utility of this inhaled antedrug approach. TRIAL REGISTRATION NUMBER: NCT01560234, NCT01818869.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.