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Introduction: Poor outcomes in COVID-19 patients (pt) are associated with C5a-C5aR axis activation. A C5a-specific monoclonal antibody, vilobelimab (VILO), improves outcomes in critically ill COVID-19 pt in a Phase 3 randomized, double-blind, placebo (PLC)- controlled study [1]. Method(s): COVID-19 pt within 48 h of intubation were randomly assigned to receive 6, 800 mg infusions of VILO or PLC at a 1:1 ratio on top of standard of care. Predefined subgroup analyses by region and country were performed. Result(s): Forty-six (46) hospitals on 4 continents randomized 369 pt: VILO (n = 178), PLC (n = 191). VILO significantly reduced 28- (HR 0.67;95% CI 0.48-0.96;p = 0.027) and 60-Day mortality (HR 0.67;95% CI 0.48-0.93, p = 0.0163) using a predefined, unstratified per protocol analysis. Mortality rates at 28- and 60-days and VILO treatment effects, however, differed substantially between regions: Western Europe HR for 60-day mortality 0.59 [0.37-0.95], South Africa plus Russian Federation HR 0.62 [0.28-1.38] and South America HR 0.80 [0.46-1.39] (Fig. 1). The weak signal in South America is predominately driven by Brazil (n = 74), which showed a significant age imbalance with a median 9-years younger PLC group (44.5-years-old vs 53.5-years-old) with low 60-day mortality of ~ 32.5% in the PLC group versus ~ 43.3% in Western Europe. Adjusting for age group categories (<= 30, 31-40, 41-50, 51-60, > 60;Cox regression) for 60-day mortality changed the HR in Brazil (0.96 [0.44-2.10] for continuous age-adjustment) to values near the estimate for the entire study population (HR 0.77 [0.35-1.69] for age in categories), suggesting a by chance imbalance and not a statistically evident weaker effect in Brazil. Conclusion(s): Regional efficacy differences between the rest of the world and South America were driven by age imbalances between treatment groups, which do not diminish the robust efficacy signal for VILO in severe COVID-19.
ABSTRACT
Introduction: C5a-C5aR axis activation is associated with increased mortality in severe COVID-19. Vilobelimab (VILO), a C5a-specific monoclonal antibody, improved mortality in severe COVID-19 patients (pts) in a Phase 3 multicenter, randomized, double-blind, placebo (PLC)- controlled study [1]. A pharmacokinetic/pharmacodynamic (PK/PD) analysis was undertaken to assess VILO and C5a as well as antidrug antibodies (ADA) levels in the study. Method(s): Forty-six (46) hospitals on four continents randomized 369 COVID-19 pts (VILO [n = 178], PLC [n = 191]) within 48 h of being mechanically ventilated to receive 6, 800 mg infusions of VILO or PLC at a 1:1 ratio on top of standard of care. Blood samples were taken at screening, Day 8 and at hospital discharge for VILO and C5a and at screening and hospital discharge for ADA. Enzyme-linked immunosorbent assays were used to analyze levels. Result(s): Screening blood samples for VILO and C5a were available for VILO (n = 93) and PLC (n = 99) from sites in Western Europe. On Day 8 after 3 infusions, mean VILO trough concentrations were 21799.3- 302972.1 ng/mL (geometric mean 137881.3 ng/mL) (Fig. 1). At screening, C5a was highly elevated and comparable between groups: VILO median 118.3 ng/mL, mean 130.3 ng/mL, PLC median 104.6 ng/mL, mean 123.2 ng/mL. By Day 8, C5a levels were reduced by 84.6% in the VILO group (median 14.5 ng/mL [mean 16.8 ng/mL], p < 0.001) versus a 19.6% increase in the PLC group (median, 119.2 ng/mL, mean 129.8 ng/ mL). Beyond Day 8, though PD sampling was sparse, C5a levels remained elevated for PLC whereas C5a slowly rose but did not reach screening levels for VILO. Treatment-induced ADA were observed in 1 pt in the VILO group (Day 40 discharge) and 1 pt in the PLC group (Day 25 discharge), both appeared independent of treatment. Conclusion(s): The PK/PD analysis shows that VILO efficiently inhibits C5a in pts with severe COVID-19 resulting in a robust clinical effect on mortality reduction without inducing ADA.
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Background: Blocking the C5a-C5aR axis in COVID-19 patients could improve outcomes by limiting myeloid cell infiltration in damaged organs and preventing excessive lung inflammation and endothelialitis. Aims and Objectives: Vilobelimab (VILO), an anti-C5a mAb that preserves the membrane attack complex (MAC), was tested in a Phase III adaptively designed multicenter, double-blind placebo (P)-controlled study for survival in critically ill COVID-19 patients. Method(s): COVID-19 pneumonia patients (N=369;VILO n=178, P n=191) within 48 hrs of intubation were randomly assigned to receive 6, 800 mg infusions of VILO or P on top of standard of care. Primary outcome was 28-day allcause mortality. Result(s): 28-day all-cause mortality was 31.7% VILO vs 41.6% P (Kaplan-Meier estimates;Cox regression site stratified, HR 0.73;95%CI:0.50-1.06;P=0.094) with a 22.7% relative mortality reduction to Day 60. In predefined primary outcome analysis without site stratification, VILO significantly reduced 28-day mortality (HR 0.67;95%CI:0.48-0.96;P=0.027);needed to treat number, 10 to save 1. VILO significantly reduced 28-day mortality in severe patients with baseline WHO ordinal scale score of 7 (n=237, HR 0.62;95%CI:0.40-0.95;P=0.028) or severe ARDS/PaO2/FiO2<=100 mmHg (n=98, HR 0.55;95%CI:0.30-0.98;P=0.044) or eGFR<60 mL/min/1.73m2 (n=108, HR 0.55;95%CI:0.31-0.96;P=0.036). Treatment emergent AEs were 90.9% VILO vs 91.0% P. Infections were comparable;VILO (62.9%), P (59.3%). Serious AEs were 58.9% VILO, 63.5% P. Conclusion(s): VILO reduced mortality at 28 to 60 days in severe COVID-19 pneumonia patients with no increase in infections suggesting the importance of targeting C5a while preserving MAC.
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The 32nd European Respiratory Society (ERS) International Congress was held again in person at the FIRA Barcelona Gran Via Conference Center in Spain, as well as online. On-site attendance was limited to 10,000 delegates, with the spaces selling out before the conference began. The program included live streamed presentations, thematic poster discussion sessions, oral presentations, mini-symposia, industry exhibitors and skills workshops to discuss major respiratory fields that included thoracic oncology, respiratory infections, interstitial lung diseases, respiratory critical care, sleep and breathing disorders and pulmonary vascular diseases. This report will cover some of the most interesting presentations related to respiratory disease treatment. Copyright © 2022 Clarivate.
ABSTRACT
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.