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

• Published in: PloS one 2020-11, Vol.15 (11), p.e0240964
• Main Authors: Siddall, Hilary, Quint, Diana, Pandya, Hitesh, Powley, Will, Shabbir, Shaila, Hohlfeld, Jens M, Singh, Dave, Lee, Laurie
• Format: Article
• Language: English
• Subjects: Adenine - administration & dosage; Adenine - adverse effects; Adenine - analogs & derivatives; Administration, Intranasal; Adult; Agonists; Agonists (Biochemistry); Allergens; Allergens - administration & dosage; Allergies; Anti-Asthmatic Agents - administration & dosage; Anti-Asthmatic Agents - adverse effects; Asthma; Asthma - drug therapy; Asthma - immunology; Asthma - physiopathology; Attenuation; Bayesian analysis; Biology and Life Sciences; Biomarkers; Bronchial Provocation Tests; Care and treatment; Clinical trials; Conditional probability; Dendritic cells; Double-Blind Method; Double-blind studies; Drug dosages; Eosinophils; Female; Forced Expiratory Volume - drug effects; Health services; Humans; Inflammation; Inflammatory diseases; Inflammatory response; Interferon; Interferon-alpha - biosynthesis; Interleukin 5; Leukocytes (eosinophilic); Male; Medicine; Medicine and Health Sciences; Middle Aged; Nitric oxide; Pharmacodynamics; Piperidines - administration & dosage; Piperidines - adverse effects; Proof of Concept Study; R&D; Receptors; Research & development; Research and Analysis Methods; Respiratory function; Rhinitis, Allergic - drug therapy; Rhinitis, Allergic - immunology; Rhinitis, Allergic - physiopathology; Sputum; Testing; Toll-Like Receptor 7 - agonists; Toll-like receptors; Young Adult
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0240964

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