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

PLoS One. 2020 Nov 9;15(11):e0240964. doi: 10.1371/journal.pone.0240964. eCollection 2020.

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.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / administration & dosage
  • Adenine / adverse effects
  • Adenine / analogs & derivatives*
  • Administration, Intranasal
  • Adult
  • Allergens / administration & dosage
  • Anti-Asthmatic Agents / administration & dosage
  • Anti-Asthmatic Agents / adverse effects
  • Asthma / drug therapy*
  • Asthma / immunology
  • Asthma / physiopathology
  • Bronchial Provocation Tests
  • Double-Blind Method
  • Female
  • Forced Expiratory Volume / drug effects
  • Humans
  • Interferon-alpha / biosynthesis
  • Male
  • Middle Aged
  • Piperidines / administration & dosage*
  • Piperidines / adverse effects
  • Proof of Concept Study
  • Rhinitis, Allergic / drug therapy
  • Rhinitis, Allergic / immunology
  • Rhinitis, Allergic / physiopathology
  • Toll-Like Receptor 7 / agonists*
  • Young Adult

Substances

  • Allergens
  • Anti-Asthmatic Agents
  • GSK2245035
  • Interferon-alpha
  • Piperidines
  • TLR7 protein, human
  • Toll-Like Receptor 7
  • Adenine

Associated data

  • ClinicalTrials.gov/NCT02833974

Grants and funding

This study (GSK study number: 205540; NCT: 02833974); was funded by GlaxoSmithKline (GSK; http://www.gsk.com), of which HS, WP and SS are employees, and DQ, HP and LL were employees at the time of study conduct. GSK was involved in the study design, data collection and analysis, and decision to publish, and preparation of the manuscript. Editorial support in the form of development of the initial draft, collating author comments, editorial suggestions to draft versions of this paper, assembling tables and figures, copyediting, referencing was provided by Gillian Wallace, MSc, at Fishawack Indicia Ltd, UK, and was funded by GSK.