The anti‐C5a antibody vilobelimab efficiently inhibits C5a in patients with severe COVID‐19

Abstract

Recently, we reported the phase II portion of the adaptive phase II/III PANAMO trial exploring potential benefit and safety of selectively blocking C5a with the monoclonal antibody vilobelimab (IFX‐1) in patients with severe coronavirus disease 2019 (COVID‐19). The potent anaphylatoxin C5a attracts neutrophils and monocytes to the infection site, causes tissue damage by oxidative radical formation and enzyme releases, and leads to activation of the coagulation system. Results demonstrated that C5a inhibition with vilobelimab was safe and secondary outcomes appeared in favor of vilobelimab. We now report the pharmacokinetic/pharmacodynamic (PK/PD) analysis of the phase II study. Between March 31 and April 24, 2020, 30 patients with severe COVID‐19 pneumonia confirmed by real‐time polymerase chain reaction were randomly assigned 1:1 to receive vilobelimab plus best supportive care or best supportive care only. Samples for measurement of vilobelimab, C3a and C5a blood concentrations were taken. Vilobelimab predose (trough) drug concentrations in plasma ranged from 84,846 to 248,592 ng/ml (571 to 1674 nM) with a geometric mean of 151,702 ng/ml (1022 nM) on day 2 and from 80,060 to 200,746 ng/ml (539 to 1352 nM) with a geometric mean of 139,503 ng/ml (939 nM) on day 8. After the first vilobelimab infusion, C5a concentrations were suppressed in the vilobelimab group (median 39.70 ng/ml 4.8 nM, IQR 33.20–45.55) as compared to the control group (median 158.53 ng/ml 19.1 nM, IQR 60.03–200.89, p = 0.0006). The suppression was maintained on day 8 ( p = 0.001). The current PK/PD analysis shows that vilobelimab efficiently inhibits C5a in patients with severe COVID‐19.

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

“…We previously showed that vilobelimab efficaciously suppressed serum C5a concentrations in this patient population. 8 Secondary outcomes of the phase 2 part of PANAMO were in favour of vilobelimab, which supported the investigation of C5a inhibition in a phase 3 trial. 7 Here, we aim to determine whether vilobelimab in addition to standard of care is efficacious in invasively mechanically ventilated patients with COVID-19.…”

Complement activation in COVID-19 and targeted therapeutic options: A scoping review

“…C5a did not statistically differ between eculizumab treated and eculizumab-free patients at day 1 and day 7. Vlaar [ 31 , 149 ], 2020 Open-label, phase 2 RCT ICU, intermediate care unit, COVID-19 ward 28-days Severe COVID-19 pneumonia (pulmonary infiltrates consistent with pneumonia, a clinical history of severe shortness of breath <14 days, or need for noninvasive or MV; P/F ratio 100–250 mmHg (n = 15) Randomized controls ( n = 15) Severe 5–7 doses of vilobelimab 800 mg IV (days 1, 2, 4, 8, 11–13, 15 and 22) Chloroquine, ganciclovir, azithromycin, heparin C5a Vilobelimab appears to be safe in patients with severe COVID-19. At day 5 after randomization, the mean P/F ratio showed no differences between treatment groups.…”

“…Infections classified as serious were reported in three (20%) of the patients treated with vilobelimab compared with five (33%) patients in the control group. C5a concentrations were suppressed in the vilobelimab group after the first dose compared to the control group, which was maintained on day eight [ 149 ].…”

“…No difference was shown in the primary endpoint of mean P/F ratio five days after randomization was observed, but secondary endpoints including mortality at day 28 seemed to be in favor of vilobelimab treatment, albeit considered preliminary. Baseline C5a concentrations were elevated in all patients and C5a was suppressed in the vilobelimab group compared with the control group, which was maintained on day eight [ 149 ]. The development of avdoralimab, a C5aR1-specific monoclonal antibody, was terminated after disappointing results of a phase 2 RCT performed in patients with different severities of COVID-19 ( NCT04371367 ) [ 13 ].…”

Highly pathogenic coronavirus N protein aggravates inflammation by MASP-2-mediated lectin complement pathway overactivation

“… 22 In another randomized, open label phase II clinical trial completed in the Netherlands by InflaRx (NCT04333420), an anti-C5a antibody (IFX-1, also known as vilobelimab 58 ) showed potential efficacy in critical COVID-19 patients, improved lymphocytopenia, and reduced lactate dehydrogenase concentrations. 58 , 59 Recently, a phase III clinical trial of vilobelimab showed a 43% reduction in 28-day all-cause mortality compared with placebo treatment in a prespecified subgroup analysis of patients in Western Europe with more severe disease ( https://www.inflarx.de/Home/Investors/Press-Releases/03-2022-InflaRx-Announces-Encouraging-Phase-III-Topline-Results-from-PANAMO-Trial-of-Vilobelimab-in-Severe-COVID-19-Patients.html ). These data further support that N protein-potentiated complement overactivation plays important roles in the pathogenesis of SARS-CoV-2.…”