AZD8848/DSP-3025 Is A Novel Potent TLR7 Agonist Ante-Drug That Demonstrates Negligible Systemic Activity And A Prolonged Period Of Control After Cessation Of Weekly Dosing In A Brown Norway Rat Ovalbumin Challenge Model

Bell, John P.; Britt, J. C.; Biffen, Mark; Ferguson, Douglas; Aoki, Mikio; Eiho, Kazuo; Bahl, Ashwani; Takaku, Haruo; Murray, Clare

doi:10.1164/ajrccm-conference.2010.181.1_meetingabstracts.a5688

Cited by 2 publications

(8 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Administration of AZD8848 directly to the lung has previously been shown to inhibit eosinophilia and IL-13 levels for up to 4 weeks post-treatment following ovalbumin challenge in the Brown Norway rat [35]. In the current study there were no significant changes observed in sputum cytokine or eosinophil counts with intranasal AZD8848 treatment 1 week post-dosing, either before or after allergen challenge.…”

Section: Discussioncontrasting

confidence: 41%

“…AZD8848 is a metabolically labile ester with a plasma half-life (t ½ ) of 2–3 min, which is rapidly converted to a weakly active metabolite in the plasma with a t ½ of 36 min [35]. The hypothesis is that there would be minimal systemic exposure and limited IFN I immune activation due to this brief half-life, resulting in a reduced incidence of side effects.…”

Section: Discussionmentioning

confidence: 99%

“…Preclinical studies in murine models [35, 36] demonstrated that intranasal administration of AZD8848 can confer sustained protection against allergen challenge. The allergen challenge model in man is an important predictor of subsequent efficacy in the treatment of asthma [37].…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Effects of the Toll-like receptor 7 (TLR7) agonist, AZD8848, on allergen-induced responses in patients with mild asthma: a double-blind, randomised, parallel-group study

et al. 2019

View full text Add to dashboard Cite

BackgroundAlthough allergic asthma is a complex area with many interacting factors involved, the ‘hygiene hypothesis’ proposes that a lack of exposure to infection during childhood may polarise the immune system towards allergen-reactive Th2-type responses in genetically susceptible individuals. Toll-like receptors (TLRs) play a key role within the innate immune system and TLR7 agonists have previously been shown to up-regulate Th1 responses and down-regulate Th2 responses to allergens in murine models of allergic or chronic asthma. This study aimed to examine the efficacy and safety of the novel TRL7 agonist AZD8848, which has been developed as an antedrug.MethodsIn this double-blind, randomised, parallel-group study, AZD8848 60 μg or placebo was administered intranasally once-weekly for 8 weeks in patients with mild-to-moderate allergic asthma (NCT00999466). Efficacy assessments were performed at 1 and 4 weeks after the last dose. The primary outcome was the late asthmatic response (LAR) fall in forced expiratory volume in 1 s (FEV1) after allergen challenge at 1-week post-treatment.ResultsAZD8848 significantly reduced average LAR fall in FEV1 by 27% vs. placebo at 1 week after treatment (p = 0.035). This effect was sustained at 4 weeks post-treatment; however, it did not reach clinical significance. AZD8848 reduced post-allergen challenge methacholine-induced airway hyper-responsiveness (AHR) vs. placebo at 1 week post-dosing (treatment ratio: 2.20, p = 0.024), with no effect at 4 weeks. There was no significant difference between the two groups in plasma cytokine, sputum Th2 cytokine or eosinophil responses post-allergen challenge at 1 week after treatment. The incidence of adverse events was similar in the two groups. AZD8848 was generally well tolerated.Conclusions and clinical relevanceIn patients with allergic asthma, TLR7 agonists could potentially reduce allergen responsiveness by stimulating Type 1 interferon responses to down-regulate the dominant Th2 responses.Trial registrationclinicaltrials.gov identifier NCT00999466.

show abstract

Section: Discussioncontrasting

confidence: 41%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Effects of the Toll-like receptor 7 (TLR7) agonist, AZD8848, on allergen-induced responses in patients with mild asthma: a double-blind, randomised, parallel-group study

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Observations involving peripheral blood mononuclear cells (PBMCs) and ovalbumin-sensitized splenocytes indicate that stimulation of TLR7 by AZD8848 inhibits Th2-adaptive responses to allergen via an immune response involving the induction of mediators including interferon alpha (IFN-α) [19-22]. Furthermore, Ikeda et al .…”

Section: Introductionmentioning

confidence: 99%

“…AZD8848 is a selective TLR7 agonist optimised for topical airway treatment through rapid metabolism by plasma esterases, thereby reducing systemic exposure [ 19 ]. Observations involving peripheral blood mononuclear cells (PBMCs) and ovalbumin-sensitized splenocytes indicate that stimulation of TLR7 by AZD8848 inhibits Th2-adaptive responses to allergen via an immune response involving the induction of mediators including interferon alpha (IFN-α) [ 19 - 22 ]. Furthermore, Ikeda et al .…”

Section: Introductionmentioning

confidence: 99%

Repeated intranasal TLR7 stimulation reduces allergen responsiveness in allergic rhinitis

Greiff¹,

Cervin²,

Ahlström-Emanuelsson³

et al. 2012

Respir Res

View full text Add to dashboard Cite

BackgroundInteractions 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.ObjectiveTo evaluate the efficacy and safety of intranasal AZD8848.MethodsIn 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.ResultsAZD8848 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.ConclusionsRepeated intranasal stimulation of Toll-like receptor 7 by AZD8848 was safe and produced a sustained reduction in the responsiveness to allergen in allergic rhinitis.Trial registrationNCT00688779 and NCT00770003 as indicated above.

show abstract

AZD8848/DSP-3025 Is A Novel Potent TLR7 Agonist Ante-Drug That Demonstrates Negligible Systemic Activity And A Prolonged Period Of Control After Cessation Of Weekly Dosing In A Brown Norway Rat Ovalbumin Challenge Model

Cited by 2 publications

References 0 publications

Effects of the Toll-like receptor 7 (TLR7) agonist, AZD8848, on allergen-induced responses in patients with mild asthma: a double-blind, randomised, parallel-group study

Effects of the Toll-like receptor 7 (TLR7) agonist, AZD8848, on allergen-induced responses in patients with mild asthma: a double-blind, randomised, parallel-group study

Repeated intranasal TLR7 stimulation reduces allergen responsiveness in allergic rhinitis

Contact Info

Product

Resources

About