Background Vilobelimab, unlike upstream complement inhibitors, blocks C5a without altering the membrane attack complex. Vilobelimab demonstrated significant mortality benefit in intubated patients with COVID-19 ARDS in a placebo-controlled study. Standard of care included corticosteroids in 97%, antithrombotic prophylaxis in 98%, and other immunomodulators in approximately 20% of the study population. The survival benefit of combined immunomodulator administration with vilobelimab is unknown. Research Question Does adding vilobelimab in patients with COVID-19 ARDS treated with tocilizumab, levilimab, or baricitinib with corticosteroids lead to improved survival? Study Design and Methods This post hoc analysis evaluated vilobelimab's effect on survival and safety in a subgroup of intubated patients with COVID-19 ARDS treated previously, concomitantly, or both with tocilizumab, levilimab, or baricitinib. Censored time-to-event variable by Kaplan-Meier type method and Cox regression analysis adjusted for age, baseline comorbidities, and ARDS severity was used to assess all-cause mortality. Results Seventy-two patients administered vilobelimab (n = 35) or placebo (n = 37) were treated before, concomitantly, or both with tocilizumab, levilimab, or baricitinib. Twenty-eight-day mortality was 9.0% for the vilobelimab plus immunomodulator subgroup vs 40.9% for the placebo plus immunomodulator group (hazard ratio [HR], 0.19; 95% CI, 0.06-0.67; P = .010). Day 60 mortality was 18.9% vs 49.3% (HR, 0.30; 95% CI, 0.12-0.77; P = .012). When patients were treated with vilobelimab and only tocilizumab (n = 30) vs placebo and tocilizumab (n = 31), 28-day mortality was 7.1% vs 42.3% (HR, 0.14; 95% CI, 0.03-0.62; P = .010), respectively. All 4 patients treated with vilobelimab and only with baricitinib survived compared with 3 of 6 patients who received placebo with baricitinib. Treatment-emergent adverse events (TEAEs) were equal in all subgroups. Serious TEAEs were reported in fewer patients in the vilobelimab plus immunomodulator group vs other subgroups. Unspecified infections occurred less frequently in the vilobelimab plus immunomodulator subgroup vs the placebo plus immunomodulator subgroup, whereas viral and fungal infections were comparable. Interpretation This small post hoc analysis suggests that vilobelimab treatment combined with tocilizumab or baricitinib potentially could improve survival in patients with COVID-19 ARDS. Combination immunomodulator therapy may have further application in broad populations of virus-induced ARDS, and these results warrant additional investigations. Clinical Trial Registration ClinicalTrials.gov; No.: NCT04333420; URL: www.clinicaltrials.gov

Background Vilobelimab, unlike upstream complement inhibitors, blocks C5a without altering the membrane attack complex. Vilobelimab demonstrated significant mortality benefit in intubated patients with COVID-19 ARDS in a placebo-controlled study. Standard of care included corticosteroids in 97%, antithrombotic prophylaxis in 98%, and other immunomodulators in approximately 20% of the study population. The survival benefit of combined immunomodulator administration with vilobelimab is unknown. Research Question Does adding vilobelimab in patients with COVID-19 ARDS treated with tocilizumab, levilimab, or baricitinib with corticosteroids lead to improved survival? Methods This post hoc analysis evaluated vilobelimab’s effect on survival and safety in a subgroup of intubated patients with COVID-19 ARDS treated previously, concomitantly, or both with tocilizumab, levilimab, or baricitinib. Censored time-to-event variable by Kaplan-Meier type method and Cox regression analysis adjusted for age, baseline comorbidities, and ARDS severity was used to assess all-cause mortality. Results Seventy-two patients administered vilobelimab (n = 35) or placebo (n = 37) were treated before, concomitantly, or both with tocilizumab, levilimab, or baricitinib. Twenty-eight-day mortality was 9.0% for the vilobelimab plus immunomodulator subgroup vs 40.9% for the placebo plus immunomodulator group (hazard ratio [HR], 0.19; 95% CI, 0.06-0.67; P = .010). Day 60 mortality was 18.9% vs 49.3% (HR, 0.30; 95% CI, 0.12-0.77; P = .012). When patients were treated with vilobelimab and only tocilizumab (n = 30) vs placebo and tocilizumab (n = 31), 28-day mortality was 7.1% vs 42.3% (HR, 0.14; 95% CI, 0.03-0.62; P = .010), respectively. All 4 patients treated with vilobelimab and only with baricitinib survived compared with 3 of 6 patients who received placebo with baricitinib. Treatment-emergent adverse events (TEAEs) were equal in all subgroups. Serious TEAEs were reported in fewer patients in the vilobelimab plus immunomodulator group vs other subgroups. Unspecified infections occurred less frequently in the vilobelimab plus immunomodulator subgroup vs the placebo plus immunomodulator subgroup, whereas viral and fungal infections were comparable. Interpretation This small post hoc analysis suggests that vilobelimab treatment combined with tocilizumab or baricitinib potentially could improve survival in patients with COVID-19 ARDS. Combination immunomodulator therapy may have further application in broad populations of virus-induced ARDS, and these results warrant additional investigations. Clinical Trial Registration ClinicalTrials.gov; No.: NCT04333420; URL: www.clinicaltrials.gov

Abstract Background Various pre-clinical and clinical studies suggest an interplay between complement C5a/C5a receptor (R1) and interleukin 6 (IL-6) signaling. C5a boosts IL-6 levels and IL-6 increases C5aR1 in inflammation and sepsis models (Fig 1). Blocking IL-6 signaling, e.g. with tocilizumab (Toci), in patients with acute coronary artery disease and with antibodies in pre-clinical studies in different tissues significantly reduces C5aR1 expression. In addition, inhibiting C5a with vilobelimab (Vilo) in COVID-19 patients with acute respiratory distress syndrome (ARDS) also improves survival as shown in a multicenter, double-blind, randomized, placebo-controlled, phase 3 trial (PANAMO, NCT04333420). COVID-19 patients with ARDS who receive Toci in addition to Vilo may serve as a model for the interplay between IL-6 and the C5a/C5aR1 axis to improve survival in ARDS.Figure 1:C5a induction of IL-6 and IL-6 induction of C5aR1. Induction of IL-6 is blocked by vilobelimab binding to C5a and tocilizumab blocks IL-6 binding to IL-6 receptor decreasing induction of C5aR1. Methods COVID-19 patients with ARDS in the Phase III PANAMO study (N=368) received up to six Vilo 800mg infusions or placebo (Plc) plus corticosteroids and anticoagulants (standard-of-care) within 48 hours of intubation over a 22-day period. A post-hoc Cox regression analysis was performed for 28- and 60-Day all-cause mortality in a subgroup of patients (n=60) who also received prior (within -7 days of Vilo administration) or concomitant Toci. Safety was also assessed.Figure 2:Kaplan Meier Survival Curve of COVID-19 Patients with ARDS Treated with Tocilizumab (Toci) prior (within 7 days) of Vilobelimab+SOC and Placebo+SOC. SOC= Standard-of-Care; corticosteroids and anticoagulants. Results Vilo+Toci (n=29) and Plc+Toci (n=31) showed point estimates for 28-Day all-cause mortality of 3.7% and 42.3% (HR 0.073; 95%CI:0.01-0.56, p=0.012), while 60-Day all-cause mortality point estimates were 15.9% and 49.1% (HR 0.245; 95%CI:0.08-0.74, p=0.013), respectively (Fig 2). Related TEAEs were similar in both groups (28.6% vs 25.8%). Serious TEAEs occurred in fewer patients receiving Vilo+Toci (42.9%) vs Plc+Toci (67.7%). Infections and infestations were slightly lower for Vilo+Toci (53.6%) vs Plc+Toci (64.5%). Conclusion This post-hoc analysis demonstrated that dual immunomodulator inhibition of the C5a/C5aR1 axis and IL-6 signaling improved survival in a subgroup of COVID-19 patients with ARDS without impacting safety. Dual immunomodulator treatment with vilobelimab and tocilizumab could potentially be used in different ARDS populations to produce a similar effect. Larger and well-controlled studies are warranted to test this hypothesis. Disclosures Roy F. Chemaly, MD/MPH, AiCuris: Advisor/Consultant|AiCuris: Grant/Research Support|Ansun Pharmaceuticals: Advisor/Consultant|Ansun Pharmaceuticals: Grant/Research Support|Astellas: Advisor/Consultant|Eurofins-Viracor: Grant/Research Support|InflaRX: Advisor/Consultant|Janssen: Advisor/Consultant|Karius: Advisor/Consultant|Karius: Grant/Research Support|Merck/MSD: Advisor/Consultant|Merck/MSD: Grant/Research Support|Moderna: Advisor/Consultant|Oxford Immunotec: Advisor/Consultant|Oxford Immunotec: Grant/Research Support|Roche/Genentech: Advisor/Consultant|Roche/Genentech: Grant/Research Support|Shinogi: Advisor/Consultant|Takeda: Advisor/Consultant|Takeda: Grant/Research Support|Tether: Advisor/Consultant Alexander Vlaar, MD, PhD, InflaRx GmbH: Advisor/Consultant Bruce P. Burnett, PhD, InflaRx Pharmaceuticals, InflaRx GmbH: Employee Camilla Chong, MD, InflaRx GmbH: Employee simon Rückinger, PhD, InflaRx GmbH: Advisor/Consultant Robert Zerbib, MSc, InflaRx GmbH: Advisor/Consultant Raymond M. Panas, PhD, InflaRx Pharmaceuticals, InflaRx GmbH: Employee Renfeng Guo, MD, InflaRx GmbH: Board Member|InflaRx GmbH: Chief Scientific Officer|InflaRx GmbH: Ownership Interest|InflaRx GmbH: Stocks/Bonds (Public Company) Niels Riedemann, MD, PhD, InflaRx GmbH: Board Member|InflaRx GmbH: Chief Executive Officer|InflaRx GmbH: Ownership Interest|InflaRx GmbH: Stocks/Bonds (Public Company) Diederik van de Beek, MD, PhD, InflaRx GmbH: Advisor/Consultant

Background Vilobelimab, a first in class C5a-specific monoclonal antibody, improved 28-day and 60-day mortality in intubated COVID-19 patients in PANAMO, a phase 3 randomised, double-blind, placebo-controlled multicentre study. All-cause mortality was pre-specified to be analysed pooling by region (western Europe, South America, South Africa/Russia).Methods Critically ill, invasively mechanically ventilated COVID-19 patients were randomised in a 1:1 ratio within 48 hours of intubation to receive vilobelimab treatment (six, 800 mg intravenous infusions) or placebo on top of standard of care. We analysed the efficacy and safety of vilobelimab based on prespecified geographic regions.Results 368 patients were randomised and analysed: 177 in the vilobelimab group and 191 in the placebo group. In western Europe (n=209), 28-day all-cause mortality was significantly lower in the vilobelimab group (21%) compared with placebo (37%) (HR 0.51 (95% CI: 0.30, 0.87), p=0.014). In South America (n=126), mortality was similar between groups (40% vs 37%; HR 0.94 (95% CI: 0.53, 1.67), p=0.83). In South Africa/Russia (n=33), mortality was 69% in the vilobelimab group and 87% in the placebo group (HR 0.62 (95% CI: 0.28, 1.38), p=0.25). Within the Brazilian subpopulation (n=74), a significant age imbalance between the vilobelimab and placebo group was detected (median 53.5 years in the vilobelimab group vs 44.5 years in the placebo group). Occurrence of treatment-emergent adverse events between regions was similar.Conclusion The most apparent 28-day all-cause mortality benefit for vilobelimab was in western Europe. Age imbalance between treatment groups in Brazil may have resulted in a lower efficacy signal for vilobelimab in South America compared with other regions. Overall, vilobelimab demonstrated a favourable safety profile and reduced mortality in critically ill, intubated COVID-19 patients, with regional variations influencing outcomes.

Abstract Background C5 convertase cleaves C5 in common complement pathways yielding the anaphylatoxin C5a and C5b, part of the membrane attack complex (MAC) that mitigates bacterial infections (Fig 1). C5 can also be cleaved “extrinsically” by other enzymes. C5a is elevated in severe COVID-19 patients (Pt). Yet, inhibiting C5 cleavage increases infections without improved survival in critically ill COVID-19 Pt (Annane et al. 2023). In addition, eculizumab, a C5 blocker does not prevent C5a from being generated in COVID-19 Pt (Raghunandan et al. 2020). Vilobelimab (Vilo), an anti-C5a monoclonal antibody that preserves MAC, was tested in a Phase 3 multicenter, double-blind, randomized, placebo (Plc)-controlled study for its effect on survival in critically ill COVID-19 Pt (Vlaar et al. 2023). Methods COVID-19 Pt recruited worldwide (N=368; Vilo n=177, Plc n=191) intubated within 48 hrs before treatment, received up to 6, 800mg infusions of Vilo or Plc on top of standard-of-care. The primary endpoint was 28-Day all-cause mortality with key secondary endpoints of 60-Day mortality and safety. Blood samples were assessed by ELISA at screening, Day 8 and at hospital discharge for Vilo and C5a levels. No meningococcal vaccination or prophylactic antibiotics were used in the study. Results Kaplan-Meier estimates showed a 28-Day mortality rate of 31.7% for Vilo vs 41.6% for Plc [HR 0.67 (95% CI: 0.48, 0.96), p< 0.05] with similar 60-Day results. On Day 8 after 3 infusions, mean Vilo trough levels were 21,799.3 to 302,972.1 ng/mL (geometric mean 137,881.3 ng/mL). C5a was highly elevated and comparable between groups at screening: Vilo mean 130.3 ng/mL, Plc mean 123.2 ng/mL. By Day 8, C5a levels were reduced 87% for Vilo (mean 16.8 ng/mL, p< 0.001) vs an increase for Plc (mean 129.8 ng/mL). Though post Day 8 sampling was sparse, C5a levels remained elevated for Plc and low for Vilo throughout the study. Serious AEs were 58.9% for Vilo and 63.5% for Plc. Treatment-emergent AEs were 90.9% for Vilo vs 91.0% for Plc. Infection incidence per 100 Pt days was comparable in both groups. Conclusion Results from this Phase 3 study show that direct C5a inhibition by vilobelimab while presumably preserving MAC, as opposed to upstream C5 blockade, results in a survival benefit for critically ill COVID-19 Pt without increasing infections. Disclosures Bruce P. Burnett, PhD, InflaRx GmbH, InflaRx Pharmaceuticals, Inc.: Employee Alexander Vlaar, MD, PhD, InflaRx: Advisor/Consultant Maria Habel, PhD, InflaRx GmbH: Employee Claus Thielert, PhD, InflaRx GmbH: Employee James Dickinson, MSc, InflaRx GmbH: Employee simon Rückinger, PhD, Metronomia Clinical Research GmbH: Advisor/Consultant Robert Zerbib, MSc, InflaRx GmbH: Advisor/Consultant Dorothee Neukirchen, PhD, InflaRx GmbH: Employee Renfeng Guo, MD, inflarx: Board Member|inflarx: I am an Inventor for Vilobelimab|inflarx: Ownership Interest|inflarx: Stocks/Bonds|InflaRx GmbH, InflaRx Pharmaceuticals, Inc.: Board Member|InflaRx GmbH, InflaRx Pharmaceuticals, Inc.: Founder|InflaRx GmbH, InflaRx Pharmaceuticals, Inc.: Employee|InflaRx GmbH, InflaRx Pharmaceuticals, Inc.: Ownership Interest Niels Riedemann, MD, PhD, InflaRx GmbH, InflaRx Pharmaceuticals, Inc.: Board Member|InflaRx GmbH, InflaRx Pharmaceuticals, Inc.: Founder|InflaRx GmbH, InflaRx Pharmaceuticals, Inc.: Employee|InflaRx GmbH, InflaRx Pharmaceuticals, Inc.: Ownership Interest

Introduction: A C5a-specific mAb, vilobelimab (VILO), in a Phase 3 randomized, double-blind, placebo (P)-controlled study showed significant reduction in 28-d all-cause mortality in critically ill COVID-19 patients (pt) (Vlaar APJ et al. Lancel Respir Med 2022;10(12):1137-46). Aims and Objectives: To compare mortality worldwide and by region in severe ARDS COVID-19 pt treated with VILO vs P. Methods: COVID-19 pt (N=368; VILO n=177, P n=191) were intubated within 48 hrs before 6, 800mg infusions of VILO or P on top of standard-of-care. Prespecified and posthoc analyses were performed worldwide and by region [Western Europe (WE), South America (SA), Russia/South Africa (RSA)] for mortality in severe ARDS pt with PaO2/FiO2<100 mmHg. Results: Median age (VILO 58 vs P 57 yrs), sex (~70% male) and severe ARDS pt were similar (VILO n=43, 24.3%; P n=55, 28.8%). VILO significantly reduced relative all-cause 28-d mortality worldwide in severe ARDS pt by 32.8% (HR 0.55; 95% CI:0.30-0.98;P=0.044). By region, VILO showed a nonsignificant 28-d mortality reduction trend (HR 0.37; 95% CI:0.11-1.22;P=0.058) in WE but SA (HR 1.03; 95% CI:0.040-2.70;P=0.944) and RSA (HR 0.37; 95% CI:0.11-1.22;P=0.102) showed lesser effects likely due to a younger P group median age in SA (VILO 50.0 vs P 45.5 yrs) and small numbers of severe ARDS pt in RSA. Treatment-emergent AEs, serious AEs and infection incidence per 100 pt days were equal per group with no meningococcal infections. Conclusion: Vilobelimab demontrated a significant worldwide reduction in all-cause mortality in severe ARDS COVID-19 pt with detected differences in three prespecified regions which may have been impacted by low pt numbers and an uneven age distribution in SA.

Abstract Background SARS-CoV-2 induces endothelial damage and activates the complement system. In severe COVID-19 patients, complement split factor C5a is highly elevated leading to inflammation that contributes to multiorgan failure. The anti-C5a monoclonal antibody, Vilobelimab (Vilo), which preserves the membrane attack complex (MAC), was investigated in an adaptively designed, randomized double-blind, placebo (P)-controlled Phase 3 international multicenter study for survival in critically ill COVID-19 patients (pts). Methods COVID-19 pneumonia pts (N=368; Vilo n=177, P n=191), mechanically ventilated within 48 hrs before treatment, received up to 6, 800 mg infusions of Vilo or P on top of standard of care. The primary and main secondary endpoints were 28-day (d) and 60-d all-cause mortality. Results Pts enrolled in the study were on corticosteroids (97%) and anti-coagulants (98%) as standard of care. A smaller proportion (20%) were either continuing or had taken immunomodulators such as tocilizumab and baricitinib prior to receiving Vilo. The 28-d all-cause mortality was 31.7% with Vilo vs 41.6% with P (Kaplan-Meier estimates; Cox regression site-stratified, HR 0.73; 95% CI:0.50-1.06; P=0.094), representing a 23.8% relative mortality reduction. In predefined primary outcome analysis without site stratification, however, Vilo significantly reduced mortality at 28 (HR 0.67; 95% CI:0.48-0.96; P=0.027) and 60 days (HR 0.67; 95% CI:0.48-0.92; P=0.016). Vilo also significantly reduced 28-d mortality in more severe pts with baseline WHO ordinal scale score of 7 (n=237, HR 0.62; 95% CI:0.40-0.95; P=0.028), severe ARDS/PaO2/FiO2 ≤ 100 mmHg (n=98, HR 0.55; 95% CI:0.30-0.98; P=0.044) and 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%. Infection incidence per 100 Pt days were equal. No meningococcal infections were reported. Serious AEs were 58.9% Vilo, 63.5% P. Conclusion Vilo significantly reduced mortality at 28 and 60 days in critically ill COVID-19 pts with no increase in infections suggesting the importance of targeting C5a while preserving MAC. Vilo targets inflammation which may represent an approach to treat sepsis and ARDS caused by other respiratory viruses. Disclosures Alexander Vlaar, MD, PhD, InflaRx GmbH: Advisor/Consultant Maria Habel, PhD, InflaRx GmbH: Stocks/Bonds Claus Thielert, PhD, InflaRx GmbH: Stocks/Bonds James Dickinson, MSc, InflaRx GmbH: Stocks/Bonds simon Rückinger, PhD, InflaRx GmbH: Advisor/Consultant Robert Zerbib, MSc, InflaRx GmbH: Stocks/Bonds Dorothee Neukirchen, PhD, InflaRx GmbH: Stocks/Bonds Korinna Pilz, MD, MSc, InflaRx GmbH: Ownership Interest|InflaRx GmbH: Stocks/Bonds Renfeng Guo, MD, InflaRx GmbH: Board Member|InflaRx GmbH: CSO|InflaRx GmbH: Ownership Interest|InflaRx GmbH: Stocks/Bonds Diederik van de Beek, MD, PhD, InflaRx GmbH: Advisor/Consultant Niels Riedemann, MD, PhD, InflaRx GmbH: Board Member|InflaRx GmbH: CEO|InflaRx GmbH: Ownership Interest|InflaRx GmbH: Stocks/Bonds.

Background Vilobelimab, an anti-C5a monoclonal antibody, was shown to be safe in a phase 2 trial of invasively mechanically ventilated patients with COVID-19. Here, we aimed to determine whether vilobelimab in addition to standard of care improves survival outcomes in this patient population. Methods This randomised, double-blind, placebo-controlled, multicentre phase 3 trial was performed at 46 hospitals in the Netherlands, Germany, France, Belgium, Russia, Brazil, Peru, Mexico, and South Africa. Participants aged 18 years or older who were receiving invasive mechanical ventilation, but not more than 48 h after intubation at time of first infusion, had a PaO 2/FiO 2 ratio of 60-200 mm Hg, and a confirmed SARS-CoV-2 infection with any variant in the past 14 days were eligible for this study. Eligible patients were randomly assigned (1:1) to receive standard of care and vilobelimab at a dose of 800 mg intravenously for a maximum of six doses (days 1, 2, 4, 8, 15, and 22) or standard of care and a matching placebo using permuted block randomisation. Treatment was not continued after hospital discharge. Participants, caregivers, and assessors were masked to group assignment. The primary outcome was defined as all-cause mortality at 28 days in the full analysis set (defined as all randomly assigned participants regardless of whether a patient started treatment, excluding patients randomly assigned in error) and measured using KaplanMeier analysis. Safety analyses included all patients who had received at least one infusion of either vilobelimab or placebo. This study is registered with ClinicalTrials.gov, NCT04333420. Findings From Oct 1, 2020, to Oct 4, 2021, we included 368 patients in the ITT analysis ( full analysis set; 177 in the vilobelimab group and 191 in the placebo group). One patient in the vilobelimab group was excluded from the primary analysis due to random assignment in error without treatment. At least one dose of study treatment was given to 364 (99%) patients (safety analysis set). 54 patients (31%) of 177 in the vilobelimab group and 77 patients (40%) of 191 in the placebo group died in the first 28 days. The all-cause mortality rate at 28 days was 32% (95% CI 25-39) in the vilobelimab group and 42% (35-49) in the placebo group (hazard ratio 0 center dot 73, 95% CI 0 center dot 50-1 center dot 06; p=0 center dot 094). In the predefined analysis without site-stratification, vilobelimab significantly reduced all-cause mortality at 28 days (HR 0 center dot 67, 95% CI 0 center dot 48-0 center dot 96; p=0 center dot 027). The most common TEAEs were acute kidney injury (35 [20%] of 175 in the vilobelimab group vs 40 [21%] of 189 in the placebo), pneumonia (38 [22%] vs 26 [14%]), and septic shock (24 [14%] vs 31 [16%]). Serious treatment-emergent adverse events were reported in 103 (59%) of 175 patients in the vilobelimab group versus 120 (63%) of 189 in the placebo group. Interpretation In addition to standard of care, vilobelimab improves survival of invasive mechanically ventilated patients with COVID-19 and leads to a significant decrease in mortality. Vilobelimab could be considered as an additional therapy for patients in this setting and further research is needed on the role of vilobelimab and C5a in other acute respiratory distress syndrome-causing viral infections.