Bruno François1, Xavier Wittebole2, Ricard Ferrer3, Jean-Paul Mira4, Thierry Dugernier5, Sébastien Gibot6,7, Marc Derive8, Aurélie Olivier8, Valérie Cuvier8, Stephan Witte9, Peter Pickkers10, François Vandenhende11, Jean-Jacques Garaud8, Miguel Sánchez12, Margarita Salcedo-Magguilli8, Pierre-François Laterre2. 1. Medical-Surgical ICU Department and Inserm CIC1435 & UMR1092, CRICS-TRIGGERSEP Network, CHU Limoges, Limoges, France. b.francois@unilim.fr. 2. Department of Critical Care Medicine, St Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium. 3. ICU Department, Vall d'Hebron University Hospital, Barcelona, Spain. 4. Medical ICU, Cochin Hotel-Dieu, AP-HP, Paris, France. 5. ICU Department, Clinique St. Pierre, Ottignies, Belgium. 6. Medical ICU Department, Hospital Central, CHU Nancy, Nancy, France. 7. Inserm U1116, Nancy Medical Faculty, Lorraine University, Nancy , France. 8. Inotrem SA, Paris, France. 9. Helion Pharma, Schriesheim, Germany. 10. ICU Department, Radboudumc Hospital, Nijmegen, The Netherlands. 11. ClinBay SPRL, Baisy-Thy, Belgium. 12. ICU Department, Hospital Clínico San Carlos, Madrid, Spain.
Abstract
PURPOSE:Nangibotide is a specific TREM-1 inhibitor that tempered deleterious host-pathogens interactions, restored vascular function, and improved survival, in animal septic shock models. This study evaluated the safety and pharmacokinetics of nangibotide and its effects on clinical and pharmacodynamic parameters in septic shock patients. METHODS: This was a multicenter randomized, double-blind, two-stage study. Patients received either continuous infusion of nangibotide (0.3, 1.0, or 3.0 mg/kg/h) or placebo. Treatment began < 24 h after shock onset and continued for up to 5 days. Safety primary outcomes were adverse events (AEs), whether serious or not, and death. Exploratory endpoints evaluated nangibotide effects on pharmacodynamics, organ function, and mortality, and were analyzed according to baseline sTREM-1 concentrations. RESULTS:Forty-nine patients were randomized. All treatment emergent AEs (TEAEs) were collected until Day 28. No significant differences were observed in TEAEs between treatment groups. No drug withdrawal linked to TEAE nor appearance of anti-drug antibodies were reported. Nangibotide pharmacokinetics appeared to be dose-proportional and clearance was dose-independent. Nangibotide did not significantly affect pharmacodynamic markers. Decrease in SOFA score LS mean change (± SE) from baseline to Day 5 in pooled nangibotide groups versus placebo was - 0.7 (± 0.85) in the randomized population and - 1.5 (± 1.12) in patients with high baseline plasma sTREM-1 concentrations (non-significant). This pattern was similar to organ support end points. CONCLUSION: No significant increases in TEAEs were detected in nangibotide-treated patients versus placebo. These results encourage further evaluation of nangibotide and further exploration of plasma sTREM-1 concentrations as a predictive efficacy biomarker.
RCT Entities:
PURPOSE:Nangibotide is a specific TREM-1 inhibitor that tempered deleterious host-pathogens interactions, restored vascular function, and improved survival, in animal septic shock models. This study evaluated the safety and pharmacokinetics of nangibotide and its effects on clinical and pharmacodynamic parameters in septic shockpatients. METHODS: This was a multicenter randomized, double-blind, two-stage study. Patients received either continuous infusion of nangibotide (0.3, 1.0, or 3.0 mg/kg/h) or placebo. Treatment began < 24 h after shock onset and continued for up to 5 days. Safety primary outcomes were adverse events (AEs), whether serious or not, and death. Exploratory endpoints evaluated nangibotide effects on pharmacodynamics, organ function, and mortality, and were analyzed according to baseline sTREM-1 concentrations. RESULTS: Forty-nine patients were randomized. All treatment emergent AEs (TEAEs) were collected until Day 28. No significant differences were observed in TEAEs between treatment groups. No drug withdrawal linked to TEAE nor appearance of anti-drug antibodies were reported. Nangibotide pharmacokinetics appeared to be dose-proportional and clearance was dose-independent. Nangibotide did not significantly affect pharmacodynamic markers. Decrease in SOFA score LS mean change (± SE) from baseline to Day 5 in pooled nangibotide groups versus placebo was - 0.7 (± 0.85) in the randomized population and - 1.5 (± 1.12) in patients with high baseline plasma sTREM-1 concentrations (non-significant). This pattern was similar to organ support end points. CONCLUSION: No significant increases in TEAEs were detected in nangibotide-treated patients versus placebo. These results encourage further evaluation of nangibotide and further exploration of plasma sTREM-1 concentrations as a predictive efficacy biomarker.
Authors: Neha A Sathe; Pavan K Bhatraju; Carmen Mikacenic; Eric D Morrell; F Linzee Mabrey; W Conrad Liles; Mark M Wurfel Journal: Shock Date: 2022-02-01 Impact factor: 3.454
Authors: Aline H de Nooijer; Inge Grondman; Simon Lambden; Emma J Kooistra; Nico A F Janssen; Matthijs Kox; Peter Pickkers; Leo A B Joosten; Frank L van de Veerdonk; Marc Derive; Sebastien Gibot; Mihai G Netea Journal: Biosci Rep Date: 2021-07-30 Impact factor: 3.840
Authors: Bruno Francois; Simon Lambden; Sebastien Gibot; Marc Derive; Aurelie Olivier; Valerie Cuvier; Stephan Witte; Jean-Marie Grouin; Jean Jacques Garaud; Margarita Salcedo-Magguilli; Mitchell Levy; Pierre-François Laterre Journal: BMJ Open Date: 2021-07-07 Impact factor: 2.692