Intranasal GSK2245035 induces prolonged reductions in nasal responsiveness to allergen

Introduction: GSK2245035, a selective toll-like receptor 7 (TLR7) agonist, may reduce allergic reactivity by inducing type 1 interferons (IFNs). Aims To examine safety, tolerability and pharmacodynamics of intranasal (IN) GSK2245035 and explore the effect on allergic nasal response. Methods Randomised, double-blind, placebo (pbo)-controlled study of 42 participants with active seasonal allergic rhinitis, receiving 8 weekly doses of IN GSK2245035 (pbo, 20ng, 80ng; n=14/group). Adverse events (AE) and nasal symptoms were assessed. IFN-inducible protein 10 (IP-10) was measured at Weeks 1 and 8, and 1 (follow-up visit [FUV]1) and 3 (FUV2) weeks post treatment. Nasal allergen challenges (NAC) were conducted at baseline, FUV1 and FUV2. Bayesian framework enabled probability statements for mean effect sizes. Results GSK2245035 induced cytokine-related AEs (pbo 28%, 20ng 36%, 80ng 93%; n=1 withdrew); headache was most common (mild: pbo 7%, 20ng 14%, 80ng 14%; moderate: pbo 7%, 20ng 14%, 80ng 29%; severe: pbo 7%, 80ng 36%). No nasal mucosa AE pattern was noted. IP-10 was increased in nasal lavage and serum (>95% certainty). GSK2245035 reduced total nasal symptom score (TNSS) 15 min post NAC with high probability at FUV1 (20ng 92%, 80ng 89%) and FUV2 (both 84%); median reductions in TNSS: 1.9, 1.8 (FUV1; 20ng, 80ng) and 1.3, 1.4 (FUV2; 20ng, 80ng). Nasal inflammatory biomarkers showed trends for reduction at FUV1 and FUV2. Conclusions IN GSK2245035 led to dose-related AEs consistent with pharmacology. 20ng was well tolerated overall; both doses well tolerated locally. Weekly TLR7 agonism reduced nasal responsiveness to allergen persisting 3 weeks post treatment. Study funded by GSK: TL7116958, [NCT01788813][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01788813&atom=%2Ferj%2F46%2Fsuppl_59%2FPA2553.atom