Background:
Interactions between Th1 and Th2 immune responses are of importance to the onset anddevelopment of allergic disorders. A Toll-like receptor 7 agonist such as AZD8848 may havepotential as a treatment for allergic airway disease by skewing the immune system away froma Th2 profile.ObjectiveTo evaluate the efficacy and safety of intranasal AZD8848.
Methods:
In a placebo-controlled single ascending dose study, AZD8848 (0.3-600 mug) was givenintranasally to 48 healthy subjects and 12 patients with allergic rhinitis (NCT00688779). In aplacebo-controlled repeat challenge/treatment study, AZD8848 (30 and 60 mug) was givenonce weekly for five weeks to 74 patients with allergic rhinitis out of season: starting 24hours after the final dose, daily allergen challenges were given for seven days(NCT00770003). Safety, tolerability, pharmacokinetics, and biomarkers were monitored.During the allergen challenge series, nasal symptoms and lavage fluid levels of tryptase andalpha2-macroglobulin, reflecting mast cell activity and plasma exudation, were monitored.
Results:
AZD8848 produced reversible blood lymphocyte reductions and dose-dependent flu-likesymptoms: 30-100 mug produced consistent yet tolerable effects. Plasma interleukin-1 receptorantagonist was elevated after administration of AZD8848, reflecting interferon productionsecondary to TLR7 stimulation. At repeat challenge/treatment, AZD8848 reduced nasalsymptoms recorded ten minutes after allergen challenge up to eight days after the final dose.Tryptase and alpha2-macroglobulin were also reduced by AZD8848.
Conclusions:
Repeated intranasal stimulation of Toll-like receptor 7 by AZD8848 was safe and produced asustained reduction in the responsiveness to allergen in allergic rhinitis.Trial registrationNCT00688779 and NCT00770003 as indicated above.
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