Phase 2, randomised placebo-controlled trial to evaluate the efficacy and safety of an anti-GM-CSF antibody (KB003) in patients with inadequately controlled asthma

Abstract

ObjectivesWe wished to evaluate the effects of an antigranulocyte-macrophage colony-stimulating factor monoclonal antibody (KB003) on forced expiratory volume in 1 s (FEV1), asthma control and asthma exacerbations in adult asthmatics inadequately controlled by long-acting bronchodilators and inhaled/oral corticosteroids.Settings47 ambulatory asthma care centres globally.Primary outcome measuresChange in FEV1 at week 24.Participants311 were screened, 160 were randomised and 129 completed the study.Interventions7 intravenous infusions of either 400 mg KB003 or placebo at baseline and weeks 2, 4, 8, 12, 16 and 20.Primary and secondary outcome measuresFEV1 at week 24, asthma control, exacerbation rates and safety in all participants as well as prespecified subgroups.Main resultsIn the KB003 treated group, FEV1 at week 24 improved to 118 mL compared with 54 mL in the placebo group (p=0.224). However, FEV1 improved to 253 vs 26 mL at week 24 (p=0.02) in eosinophilic asthmatics (defined as >300 peripheral blood eosinophils/mL at baseline) and comparable improvements were seen at weeks 20 (p=0.034) and 24 (p=0.077) in patients with FEV1 reversibility ≥20% at baseline and at weeks 4 (p=0.029), 16 (p=0.018) and 20 (p=0.006) in patients with prebronchodilator FEV1 ≤50% predicted at baseline. There were no effects on asthma control or exacerbation rates. The most frequent adverse events in the KB003 group were rhinosinusitis and headache. There was no significant difference in antidrug antibody response between placebo and treated groups. There were no excess infections or changes in biomarkers known to be associated with the development of pulmonary alveolar proteinosis.ConclusionsHigher doses and/or further asthma phenotyping may be required in future studies with KB003.Trial registration numberNCT01603277; Results.

Neutrophils are a major source of the epithelial barrier disrupting cytokine oncostatin M in patients with mucosal airways disease

“…They did not observe improved forced expiratory volume in 1 second (FEV 1 ) in the entire patient cohort. However, when they separated patients based on markers of poorly controlled asthma, peripheral blood eosinophilia, low baseline FEV 1 , and high bronchodilator reversibility, they did detect an improvement in FEV 1 in response to treatment with KB003 51 .…”

Insights in particulate matter‐induced allergic airway inflammation: Focus on the epithelium

“…In addition to standard therapy, poor‐controlled, severe asthmatics with a specific asthmatic phenotype are treated with a few approved biologics, that is anti‐IgE (omalizumab) or anti‐IL‐5 (mepolizumab or reslizumab)) . Moreover, also several biologics that target the type 2‐promoting cytokines, such as anti‐TSLP (tezepelumab), anti‐GM‐CSF and anti‐IL‐33, have entered (pre)clinical trials to evaluate their efficacy as add‐on therapy in asthmatics. Intriguingly, as severe asthmatic phenotypes are associated with exposure to air pollutants, microbes and glycolipids, this raises the hypothesis that these biologicals would also be beneficial within the context of PM exposure.…”

The epithelial barrier and immunoglobulin A system in allergy

“…Overexpression of GM‐CSF in mice induces spontaneous Th2 sensitization to ovalbumin independently of IL‐4, while GM‐CSF −/− mice show a clear lack of airway eosinophils , antibody‐driven GM‐CSF neutralization preventing their sensitization to HDM . Despite the ubiquitous distribution of GM‐CSF, an anti‐GM‐CSF monoclonal antibody has been tested recently in a phase‐II trial , to evaluate its efficacy and safety in patients with inadequately controlled asthma, but no improvement in lung function was observed in this study.…”