A randomized double blind, placebo controlled phase 2 trial of BIIL 284 BS (an LTB4 receptor antagonist) for the treatment of lung disease in children and adults with cystic fibrosis

Abstract

Background Airway inflammation, mediated in part by LTB4, contributes to lung destruction in patients with cystic fibrosis (CF). LTB4-receptor inhibition may reduce airway inflammation. We report the results of a randomized, double-blind, placebo-controlled study of the efficacy and safety of the leukotriene B4 (LTB4)-receptor antagonist BIIL 284 BS in CF patients. Methods CF patients age ≥ 6 years with mild to moderate lung disease were randomized to oral BIIL 284 BS or placebo once daily for 24 weeks. Co-primary endpoints were change in FEV1 and incidence of pulmonary exacerbation. Results After 420 (155 children, 265 adults) of the planned 600 patients were randomized, the trial was terminated after a planned interim analysis revealed a significant increase in pulmonary related serious adverse events (SAE) in adults receiving BIIL 284 BS. Final analysis revealed SAEs in 36.1% of adults receiving BIIL 284 BS vs. 21.2% receiving placebo (p=0.007), and in 29.6% of children receiving BIIL 284 BS vs. 22.9% receiving placebo (p= 0.348). In adults, the incidence of protocol-defined pulmonary exacerbation was greater in those receiving BIIL 284 BS than in those receiving placebo (33.1% vs. 18.2% respectively; p=0.005). In children, the incidence of protocol-defined pulmonary exacerbation was 19.8% in the BIIL 284 BS arm, and 25.7% in the placebo arm (p=0.38). Conclusions While the cause of increased SAEs and exacerbations due to BIIL 284 BS is unknown, the outcome of this trial provides a cautionary tale for the administration of potent anti-inflammatory compounds to individuals with chronic infections, as the potential to significantly suppress the inflammatory response may increase the risk of infection-related adverse events.

Connectivity mapping (ssCMap) to predict A20-inducing drugs and their antiinflammatory action in cystic fibrosis

“…We have shown here that sscMap is a potent tool to predict effective drugs that can modify A20 without totally inhibiting NF-κB. This is particularly important in the clinical setting, as pharmacological suppression of inflammation may increase the incidence of infective exacerbations (52).…”

Microbiota-Driven Immune Cellular Maturation Is Essential for Antibody-Mediated Adaptive Immunity to Staphylococcus aureus Infection in the Eye

“…While this result suggests that limiting pathology by inhibiting PMN influx might be beneficial, the increased bacterial burdens and likelihood of dissemination to extraocular tissues (25) in the face of PMN deficiencies likely preclude such an approach. An analogous situation was found in humans, wherein inhibition of neutrophil influx into the lungs of cystic fibrosis (CF) patients infected with P. aeruginosa by an experimental anti-inflammatory drug, BIIL 284 (26), resulted in early termination of the clinical trial due to worse outcomes in treated patients (27).…”

Management of bronchiectasis in adults

“…Interestingly, the study reported higher airway inflammation despite reduced neutrophils and an increase in discontinuation due to infections [108]. One concern regarding anti-inflammatory drugs has been the potential that reducing neutrophil numbers could lead to uncontrolled bacterial infection, as occurred in a previous trial of a leukotriene B4 receptor antagonist in cystic fibrosis [109,110]. Statins have immunomodulatory effects and may have a role in neutrophilic inflammation.…”