Anti-C5a antibody (vilobelimab) therapy for critically ill, invasively mechanically ventilated patients with COVID-19 (PANAMO): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial

Vlaar, Alexander P.J.; Witzenrath, Martin; Paassen, Pieter van; Heunks, Leo; Mourvillier, Bruno; Bruin, Sanne de; Lim, Endry H T; Brouwer, Matthijs C.; Tuinman, Pieter R.; Saraiva, José Francisco Kerr; Marx, Gernot; Lobo, Suzana M.; Boldo, Rodrigo; Campos, Jesus Abraham Simón; Cornet, Alexander D.; Grebenyuk, Anastasia; Engelbrecht, Johannes M; Mukansi, Murimisi; Zerbib, Robert; Rückinger, Simon; Pilz, Korinna; Guo, Renfeng; Beek, Diederik van de; Riedemann, Niels C.

doi:10.1016/s2213-2600(22)00297-1

Cited by 84 publications

(77 citation statements)

References 26 publications

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“…We recently reported positive results from the multicentre, double-blind, randomised, placebo-controlled, phase 3 PANAMO trial in which we targeted complement 5a (C5a) with vilobelimab, an anti-C5a monoclonal antibody, in critically ill, invasively mechanically ventilated patients with COVID-19 [ 1 ]. The addition of vilobelimab to best supportive care (BSC) improved survival and led to a significant decrease in mortality [ 1 ]. C5a is an important contributor to the innate immune system and has the potency to activate the coagulation system [ 2 , 3 ].…”

Section: Introductionmentioning

confidence: 99%

Anti-C5a antibody vilobelimab treatment and the effect on biomarkers of inflammation and coagulation in patients with severe COVID-19: a substudy of the phase 2 PANAMO trial

et al. 2022

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We recently reported in the phase 3 PANAMO trial that selectively blocking complement 5a (C5a) with vilobelimab led to improved survival in critically ill COVID-19 patients. C5a is an important contributor to the innate immune system and can also activate the coagulation system. High C5a levels have been reported in severely ill COVID-19 patients and correlate with disease severity and mortality. Previously, we assessed the potential benefit and safety of vilobelimab in severe COVID-19 patients. In the current substudy of the phase 2 PANAMO trial, we aim to explore the effects of vilobelimab on various biomarkers of inflammation and coagulation. Between March 31 and April 24, 2020, 17 patients with severe COVID-19 pneumonia were enrolled in an exploratory, open-label, randomised phase 2 trial. Blood markers of complement, endothelial activation, epithelial barrier disruption, inflammation, neutrophil activation, neutrophil extracellular trap (NET) formation and coagulopathy were measured using enzyme-linked immunosorbent assay (ELISA) or utilizing the Luminex platform. During the first 15 days after inclusion, change in biomarker concentrations between the two groups were modelled with linear mixed-effects models with spatial splines and compared. Eight patients were randomized to vilobelimab treatment plus best supportive care (BSC) and nine patients were randomized to BSC only. A significant decrease over time was seen in the vilobelimab plus BSC group for C5a compared to the BSC only group (p < 0.001). ADAMTS13 levels decreased over time in the BSC only group compared to the vilobelimab plus BSC group (p < 0.01) and interleukin-8 (IL-8) levels were statistically more suppressed in the vilobelimab plus BSC group compared to the BSC group (p = 0.03). Our preliminary results show that C5a inhibition decreases the inflammatory response and hypercoagulability, which likely explains the beneficial effect of vilobelimab in severe COVID-19 patients. Validation of these results in a larger sample size is warranted.

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Section: Introductionmentioning

confidence: 99%

Anti-C5a antibody vilobelimab treatment and the effect on biomarkers of inflammation and coagulation in patients with severe COVID-19: a substudy of the phase 2 PANAMO trial

et al. 2022

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“…Previous reports have shown that the blockade of C5a is able to completely suppress C5a-elicited inflammation [ 14 – 16 , 23 ]. IFX-1 infusion suppressed the elevated C5a level in severe COVID-19 patients to normal for 8 days[ 20 ], and improved the survival of patients with severe COVID-19 [ 19 , 24 ]. Therefore, BDB-001 has the potential to be effective against COVID-related ARDs, by inhibiting the C5a-mediated inflammatory cytokines, and following complement activation often observed in severe COVID-19 patients [ 4 , 5 , 7 ].…”

Section: Discussionmentioning

confidence: 99%

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Anti-C5a Antibody BDB-001 for Severe COVID-19: A Randomized, Double-Blind, Placebo-Controlled Phase 1 Clinical Trial in Healthy Chinese Adults

Chen

Dai

et al. 2023

Infect Dis Ther

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Introduction Severe Coronavirus Disease 2019 (COVID-19) progresses with inflammation and coagulation, due to an overactive complement system. Complement component 5a (C5a) plays a key role in the complement system to trigger a powerful “cytokine and chemokine storm” in viral infection. BDB-001, a recombinant human immunoglobulin G4 (IgG4) that specially binds to C5a, has the potential to inhibit the C5a-triggered cytokine storm in treating COVID-19 patients and other inflammation diseases. Here, we have explored its safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy adults. This trial is registered with http://www.chinadrugtrials.org.cn/(CTR20200429 ). Methods Thirty-two enrolled participants were randomized into three single-dose cohorts (2, 4, and 8 mg/kg) and 1 multi-dose cohort (4 mg/kg), and received either BDB-001 or placebo (3:1) double-blindly. The safety and tolerability after administration were evaluated for 21 days for single-dose cohorts and 28 days for the multi-dose cohort. The pharmacokinetics of BDB-001 in plasma and pharmacodynamics as free C5a in plasma were analyzed. Results The incidence of drug-related adverse events (AEs) was low, and all AEs were mild or moderate: neither AEs ≥ 3 (NCI-Common Terminology Criteria For Adverse Events, CTCAE 5.0) nor serious adverse events (SAEs) were found. The area under the concentration–time curve from time zero to 480 h (AUC 0-480h ), that from time zero to infinity (AUC inf ), and peak plasma concentration © max ) increased dose-dependently from 2 to 8 mg/kg in the single-dose cohorts and were characterized by a nonlinear pharmacokinetics of target-mediated drug disposal (TMDD). The accumulation index by AUC 0-tau after five administrations (4 mg/kg) from the multi-dose cohort was 6.42, suggesting an accumulation effect. Furthermore, inhibition of C5a at the plasma level was observed. Conclusion The results of this phase I study supported that BDB-001 is a potent anti-C5a inhibitor with safety, tolerability, and no immunogenicity. Trial Registration Number CTR20200429. Supplementary Information The online version contains supplementary material available at 10.1007/s40121-023-00759-4.

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“…13,14 Based on this cumulative evidence from randomised trials, antivirals and immunomodulatory agents have become part of the standard of care for the treatment of COVID-19. 15 Alexander Vlaar and colleagues 16 performed a placebocontrolled, double-blind, randomised phase 3 trial to evaluate the complement C5a inhibitor vilobelimab plus standard of care versus placebo plus standard of care, with 28-day mortality as the primary outcome. Frequency and severity of adverse events were similar between the groups, study drug discontinuation was 2% in each group (four [2%] patients in the vilobelimab group vs three [2%] in the placebo group), and the attrition rate was 5% (nine [5%] vs nine [5%]).…”

Section: Complement C5a Inhibition: a New Form Of Covid-19 Treatment ...mentioning

confidence: 99%

“…Alexander Vlaar and colleagues 16 performed a placebo-controlled, double-blind, randomised phase 3 trial to evaluate the complement C5a inhibitor vilobelimab plus standard of care versus placebo plus standard of care, with 28-day mortality as the primary outcome. The study enrolled 369 patients in mechanical ventilation with COVID-19 from 46 hospitals in eight countries from October, 2020, to October, 2021.…”

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confidence: 99%

Complement C5a inhibition: a new form of COVID-19 treatment for mechanically ventilated patients?

Kalil¹,

Proschan²

2022

The Lancet Respiratory Medicine

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Anti-C5a antibody (vilobelimab) therapy for critically ill, invasively mechanically ventilated patients with COVID-19 (PANAMO): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial

Cited by 84 publications

References 26 publications

Anti-C5a antibody vilobelimab treatment and the effect on biomarkers of inflammation and coagulation in patients with severe COVID-19: a substudy of the phase 2 PANAMO trial

Anti-C5a antibody vilobelimab treatment and the effect on biomarkers of inflammation and coagulation in patients with severe COVID-19: a substudy of the phase 2 PANAMO trial

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Anti-C5a Antibody BDB-001 for Severe COVID-19: A Randomized, Double-Blind, Placebo-Controlled Phase 1 Clinical Trial in Healthy Chinese Adults

Complement C5a inhibition: a new form of COVID-19 treatment for mechanically ventilated patients?

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