A nebulised antitumour necrosis factor receptor-1 domain antibody in patients at risk of postoperative lung injury: A randomised, placebo-controlled pilot study

Abstract

BACKGROUND Tumour necrosis factor receptor 1 (TNFR1) signalling mediates the cell death and inflammatory effects of TNF-α. OBJECTIVE The current clinical trial investigated the effects of a nebulised TNFR1 antagonist (GSK2862277) on signs of lung injury in patients undergoing oesophagectomy. DESIGN Randomised double-blind (sponsor unblind), placebo-controlled, parallel group study. SETTING Eight secondary care centres, the United Kingdom between April 2015 and June 2017. PATIENTS Thirty-three patients undergoing elective transthoracic oesophagectomy. INTERVENTIONS Patients randomly received a single nebulised dose (26 mg) of GSK2862277 ( n = 17) or placebo ( n = 16), given 1 to 5 h before surgery; 14 and 16, respectively competed the study. MAIN OUTCOME MEASUREMENTS Physiological and biochemical markers of lung injury, pharmacokinetic and safety endpoints were measured. The primary endpoint was the change from baseline in pulmonary vascular permeability index (PVPI) at completion of surgery, measured using single-indicator transpulmonary thermodilution. Adjusted point estimates and 95% credible intervals (analogous to conventional confidence intervals) were constructed for each treatment using Bayesian statistical models. RESULTS The mean change (with 95% credible intervals) from baseline in PVPI on completion of surgery was 0.00 (−0.23, 0.39) in the placebo and 0.00 (−0.24, 0.37) in the GSK2862277 treatment groups. There were no significant treatment-related differences in PaO 2 /F i O 2 or Sequential Organ Failure Assessment score. Levels of free soluble TNFR1, Macrophage Inflammatory Protein-1 alpha and total protein were significantly reduced in the bronchoalveolar lavage fluid of patients treated with GSK2862277 (posterior probability of decrease with GSK2862277 vs. placebo:≥0.977; equivalent to P < 0.05). The frequency of adverse events and serious adverse events were distributed evenly across the two treatment arms. CONCLUSION Pre-operative treatment with a single 26 mg inhaled dose of GSK2862277 did not result in significantly lower postoperative alveolar capillary leak or extra vascular lung water. Unexpectedly small increases in transpulmonary thermodilution-measured PVPI and extra vascular lung water index at completion of surgery suggest less postoperative lung injury than historically reported, which may have also compromised a clear assessment of efficacy in this trial. GSK2862277 was well tolerated, resulted in expected lung exposure and reduced biomarkers of lung permeability and inflammation. TRIAL REGISTRATION clinicaltrials.gov: NCT02221037.

Pulmonary Delivery of Biological Drugs

“…Significant reductions in the concentrations of inflammatory cytokines were also observed in bronchoalveolar lavage and serum [38]. In contrast, prophylactic treatment of a single dose of GSK2862277, a modified version of GSK1995057, did not reduce the postoperative alveolar capillary leak in patients following oesophagectomy [93]. The therapeutic potential of anti-TNFR1 dAb in ALI requires further investigation.…”

“…Therefore, an antibody derivative (GSK2862277) with reduced binding frequency to HAVH autoantibodies was produced and investigated in clinical trials. A single dose of inhaled GSK2862277 was well tolerated in patients with risk of ALI [93].…”

“…Several inhaled antibody fragments have entered clinical-trial stage for the treatment of acute lung injury [38,93] and asthma [45]. In a Phase I clinical trial, healthy human subjects were received a single dose of nebulised GSK1995057, a dAb directed against TNFR1, without experiencing any serious or unexpected side effects.…”

The Role of Circadian Clock Genes in Critical Illness: The Potential Role of Translational Clock Gene Therapies for Targeting Inflammation, Mitochondrial Function, and Muscle Mass in Intensive Care

“…Furthermore, TNFa is implicated in VALI with evidence that the blockade of TNFa is protective ( Proudfoot et al, 2018 ; Bertok et al, 2012 ). A phase II human trial of anti-TNFa was stopped due to being underpowered ( Ryan et al, 2020 ); however, this was recent, and so far no further human trials have been published. TNFa mediates its actions mainly through the NFkB pathway ( Liu et al, 2000 ; Zhang et al, 2017 ), and REVERB agonists have been shown to target this intracellular cascade, for example by binding to p65 at its promoter in macrophages ( Wang et al, 2018 ).…”

Restricted, optimized or liberal fluid strategy in thoracic surgery

“…With modern surgical and anesthesia care including minimally-invasive approaches, protective mechanical ventilation and avoidance of excessive hydration, the risk to damage the capillary-alveolar barrier is attenuated as shown by limited shedding of the EGL, small increase in extravascular lung water and in permeability vascular index after thoracic procedures. [ 45 46 ]…”