2. Academic Validation
  3. Efficacy and Safety of Vilobelimab (IFX-1), a Novel Monoclonal Anti-C5a Antibody, in Patients With Early Severe Sepsis or Septic Shock-A Randomized, Placebo-Controlled, Double-Blind, Multicenter, Phase IIa Trial (SCIENS Study)

Efficacy and Safety of Vilobelimab (IFX-1), a Novel Monoclonal Anti-C5a Antibody, in Patients With Early Severe Sepsis or Septic Shock-A Randomized, Placebo-Controlled, Double-Blind, Multicenter, Phase IIa Trial (SCIENS Study)

  • Crit Care Explor. 2021 Nov 17;3(11):e0577. doi: 10.1097/CCE.0000000000000577.
Michael Bauer 1 2,  Andreas Weyland 3,  Gernot Marx 4,  Frank Bloos 1 2,  Stephan Weber 5,  Norbert Weiler 6,  Stefan Kluge 7,  Anja Diers 8,  Tim Philipp Simon 4,  Ingmar Lautenschläger 6,  Matthias Gründling 9,  Ulrich Jaschinski 10,  Philipp Simon 11,  Axel Nierhaus 7,  Onnen Moerer 12,  Lorenz Reill 13,  Achim Jörres 14 15,  Renfeng Guo 16,  Markus Loeffler 17,  Konrad Reinhart 18,  Niels Riedemann 16
Affiliations

Affiliations

  • 1 Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany.
  • 2 Center for Sepsis Control & Care, Jena University Hospital, Jena, Germany.
  • 3 Research Center Neurosensory Science, Carl von Ossietzky Universität Oldenburg, Oldenburg, Germany.
  • 4 Department of Intensive and Intermediate Care Medicine, University Hospital RWTH Aachen, Aachen, Germany.
  • 5 ACOMED statistik, Leipzig, Germany.
  • 6 Department of Anesthesiology and Intensive Care Medicine, University Medical Center Kiel, Kiel, Germany.
  • 7 Department of Intensive Care Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
  • 8 Department of Anesthesiology/Intensive Care Medicine/Emergency Medicine/Pain Therapy, University Hospital Oldenburg, Oldenburg, Germany.
  • 9 Department of Anesthesiology and Intensive Care Medicine, University Hospital Greifswald, Greifswald, Germany.
  • 10 Department of Anesthesiology and Surgical Intensive Care Medicine, University Hospital Augsburg, Augsburg, Germany.
  • 11 Department of Anesthesiology and Intensive Care Medicine, University of Leipzig Medical Centre, Leipzig, Germany.
  • 12 Department of Anesthesiology, University Medical Center, Georg-August-University Göttingen, Göttingen, Germany.
  • 13 Department of Internal Medicine/Cardiology, Angiology, Nephrology, and Conservative Intensive Care Medicine, Vivantes Klinikum Neukölln, Berlin, Germany.
  • 14 Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany.
  • 15 Department of Medicine I, Nephrology, Transplantation and Medical Intensive Care, University Witten/Herdecke, Medical Center Cologne-Merheim, Cologne, Germany.
  • 16 InflaRx GmbH, Jena, Germany.
  • 17 Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
  • 18 Department of Anesthesiology and Intensive Care Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany.
PMID: 34806021 DOI: 10.1097/CCE.0000000000000577
Abstract

Anaphylatoxin C5a, a proinflammatory complement split product, plays a central role in mediating organ dysfunction.

Objectives: This phase II clinical trial was conducted to study safety, tolerability, pharmacokinetics, and pharmacodynamics of vilobelimab, a recombinant monoclonal antibody against C5a, in patients with severe sepsis or septic shock.

Design: Multicenter, randomized, and placebo-controlled study.

Setting and participants: Eleven multidisciplinary ICUs across Germany. Adult patients with severe sepsis or septic shock and with early onset of infection-associated organ dysfunction.

Main outcomes and measures: Patients were randomly assigned in a ratio of 2:1 to three subsequent dosing cohorts for IV vilobelimab or placebo receiving either 2 × 2 mg/kg (0 and 12 hr), 2 × 4 mg/kg (0 and 24 hr), and 3 × 4 mg/kg (0, 24, and 72 hr). Co-primary endpoints were pharmacodynamics (assessed by C5a concentrations), pharmacokinetics (assessed by vilobelimab concentrations), and safety of vilobelimab. Preliminary efficacy was evaluated by secondary objectives.

Results: Seventy-two patients were randomized (16 patients for each vilobelimab dosing cohort and eight patients for each placebo dosing cohort). Vilobelimab application was associated with dosing dependent decrease in C5a compared with baseline (p < 0.001). Duration of C5a decrease increased with more frequent dosing. Membrane attack complex lysis capacity measured by 50% hemolytic complement was not affected. Vilobelimab was well tolerated with similar safety findings in all dose cohorts. No vilobelimab-specific adverse events emerged. For vilobelimab-treated patients, investigators attributed less treatment-emergent adverse events as related compared with placebo. Dosing cohorts 2 and 3 had the highest ICU-free and ventilator-free days. There was no difference in mortality, vasopressor-free days, or renal replacement therapy-free days between the groups.

Conclusions and relevance: Administration of vilobelimab in patients with severe sepsis and septic shock selectively neutralizes C5a in a dose-dependent manner without blocking formation of the membrane attack complex and without resulting in detected safety issues. The data warrant further investigation of C5a inhibition in sepsis.

Keywords

adult; antibodies; complement C5a; humans; monoclonal; sepsis/*drug therapy/immunology; treatment outcome.

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