Intranasal GSK2245035, a Toll-like receptor 7 agonist, does not attenuate the allergen-induced asthmatic response in a randomized, double-blind, placebo-controlled experimental medicine study

Abstract

Background: Allergic asthma is a heterogenous disorder predominantly driven by a type 2 inflammatory response to aeroallergens. Therapeutic modulation to rebalance these type 2 responses may offer clinical benefit for allergic respiratory inflammatory diseases, with the potential for disease modification. GSK2245035, a selective toll-like receptor-7 agonist, preferentially stimulates the induction of type 1 interferon alpha, reducing type 2 responses.

Objective: This study investigated whether intranasal GSK2245035 reduced allergen-induced bronchial reactivity in mild allergic asthma.

Methods: This double-blind, placebo-controlled, parallel-group Phase IIa trial randomized (1:1) participants with mild allergic asthma to intranasal GSK2245035 20 ng or placebo once weekly for 8 weeks; follow-up was conducted 1, 4, and 12 weeks after treatment. Allergen-induced late asthmatic response 1 week after treatment was measured as minimum and weighted mean forced expiratory volume in 1 second (FEV1) 4-10 hours following bronchial allergen challenge (primary endpoint). Pharmacodynamic and allergic biomarkers, and adverse events, were assessed. A Bayesian analysis framework was used; a posterior probability >0.7 denoted primary endpoint success.

Results: Thirty-six participants were randomized (GSK2245035, n = 22; placebo, n = 14). The percentage attenuation in late asthmatic response was -4.6% (posterior probability: 0.385) and -10.5% (posterior probability: 0.303) for minimum and weighted mean FEV1, respectively. Type 2 responses were confirmed by changes in lung function, eosinophils (blood and sputum), interleukin-5 (sputum) and fractional exhaled nitric oxide biomarkers pre- and post-bronchial allergen challenge. However, no treatment effect was observed. Adverse events were reported by 10/14 (71%) and 21/22 (95%) participants in the placebo and GSK2245035 groups, respectively; headache was the most common.

Conclusions and clinical relevance: Although target engagement was observed, weekly intranasal GSK2245035 20 ng for 8 weeks did not substantially attenuate the late asthmatic response in participants with mild allergic asthma. Overall, treatment was well tolerated.

Trial registration: ClinicalTrials.gov NCT02833974.

Fig 1. Summary of participant disposition (all participants population).

^aReasons for exclusion in placebo arm: incorrect dose of allergen administered at BAC (n = 2; minor difference of 5 SBU/mL), missed one of the planned doses (n = 1), missed first follow-up visit for personal reasons (n = 1). Reasons for exclusion in GSK2245035 arm: missed one of the planned doses (n = 2), challenge not performed for safety (n = 2; FEV₁ value was too low to permit the challenge to proceed), exceeded average short-acting ß₂-agonist usage (>2 days per week) during on-treatment period to follow-up visit 3 (n = 1) ITT, intent-to-treat.

Fig 2. Study design.

BAC, bronchial allergen challenge; IC, intradermal challenge; NAC, nasal allergen challenge; DV, dosing visit; FUV, follow-up visit.

Fig 3. Mean FEV₁, change from baseline FEV₁ (following saline inhalation) per time point (per-protocol population).

95% CIs were computed separately for each treatment arm per time point from raw data values. Shaded areas are 95% CIs from each time point merged together FEV₁, forced expiratory volume in 1 second, FUV, follow-up visit; h, hours; SV, screening visit.

Fig 4. Summary profiles of allergen-induced changes in T2 inflammatory biomarkers pre- and post-bronchial allergen challenge at each time point: A) blood eosinophils; B) sputum eosinophils; C) sputum IL-5^a; D) FeNO (all participants population; B shows data from sputum-producers only).

^aThe LLQ for IL-5 was 0.19 ng/L. All IL-13 levels were below LLQ (2.22 ng/L), with the exception of one sample. 24h, 24 hours; BAC, bronchial allergen challenge; FeNO, fractional exhaled nitric oxide; IL-5, interleukin-5; FUV, follow-up visit; LLQ, lower limit of quantification; ppb, parts per billion; SV, screening visit.