Repeated intranasal TLR7 stimulation reduces allergen responsiveness in allergic rhinitis.
BACKGROUND
Interactions between Th1 and Th2 immune responses are of importance to the onset and development of allergic disorders. A Toll-like receptor 7 agonist such as AZD8848 may have potential as a treatment for allergic airway disease by skewing the immune system away from a Th2 profile.


OBJECTIVE
To evaluate the efficacy and safety of intranasal AZD8848.


METHODS
In a placebo-controlled single ascending dose study, AZD8848 (0.3-600 μg) was given intranasally to 48 healthy subjects and 12 patients with allergic rhinitis (NCT00688779). In a placebo-controlled repeat challenge/treatment study, AZD8848 (30 and 60 μg) was given once weekly for five weeks to 74 patients with allergic rhinitis out of season: starting 24 hours 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 and α2-macroglobulin, reflecting mast cell activity and plasma exudation, were monitored.


RESULTS
AZD8848 produced reversible blood lymphocyte reductions and dose-dependent flu-like symptoms: 30-100 μg produced consistent yet tolerable effects. Plasma interleukin-1 receptor antagonist was elevated after administration of AZD8848, reflecting interferon production secondary to TLR7 stimulation. At repeat challenge/treatment, AZD8848 reduced nasal symptoms recorded ten minutes after allergen challenge up to eight days after the final dose. Tryptase and α2-macroglobulin were also reduced by AZD8848.


CONCLUSIONS
Repeated intranasal stimulation of Toll-like receptor 7 by AZD8848 was safe and produced a sustained reduction in the responsiveness to allergen in allergic rhinitis.


BACKGROUND
NCT00688779 and NCT00770003 as indicated above.
Department of ORL, Head & Neck Surgery, Skane University Hospital, Lund, Sweden. lennart.greiff@live.se
Lennart
L
Greiff
Anders
A
Cervin
Cecilia
C
Ahlström-Emanuelsson
Gun
G
Almqvist
Morgan
M
Andersson
Jan
J
Dolata
Leif
L
Eriksson
Edward
E
Högestätt
Anders
A
Källén
Per
P
Norlén
Inga-Lisa
IL
Sjölin
Henrik
H
Widegren
D000281:Administration, Intranasal; D000328:Adult; D000485:Allergens / Q000008:administration & dosage*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D065631:Rhinitis, Allergic; D012221:Rhinitis, Allergic, Perennial / Q000517:prevention & control*; D051199:Toll-Like Receptor 7 / Q000008:administration & dosage* / Q000819:agonists; D055815:Young Adult
D000485:Allergens; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7