Efficacy and safety of MAS825 (anti-IL-1ß/IL-18) in COVID-19 patients with pneumonia and impaired respiratory function.

MAS825, a bispecific IL-1ß/IL-18 monoclonal antibody, could improve clinical outcomes in COVID-19 pneumonia by reducing inflammasome-mediated inflammation. Hospitalized non-ventilated patients with COVID-19 pneumonia (n = 138) were randomized (1:1) to receive MAS825 (10 mg/kg single i.v.) or placebo in addition to standard of care (SoC). The primary endpoint was the composite Acute Physiology and Chronic Health Evaluation II (APACHE II) score on Day 15 or on the day of discharge (whichever was earlier) with worst-case imputation for death. Other study endpoints included safety, C-reactive protein (CRP), SARS-CoV-2 presence, and inflammatory markers. On Day 15, the APACHE II score was 14.5 ± 1.87 and 13.5 ± 1.8 in the MAS825 and placebo groups, respectively (P = 0.33). MAS825 + SoC led to 33% relative reduction in intensive care unit (ICU) admissions, ~1 day reduction in ICU stay, reduction in mean duration of oxygen support (13.5 versus 14.3 days), and earlier clearance of virus on Day 15 versus placebo + SoC group. On Day 15, compared with placebo group, patients treated with MAS825 + SoC showed a 51% decrease in CRP levels, 42% lower IL-6 levels, 19% decrease in neutrophil levels, and 16% lower interferon-γ levels, indicative of IL-1ß and IL-18 pathway engagement. MAS825 + SoC did not improve APACHE II score in hospitalized patients with severe COVID-19 pneumonia; however, it inhibited relevant clinical and inflammatory pathway biomarkers and resulted in faster virus clearance versus placebo + SoC. MAS825 used in conjunction with SoC was well tolerated. None of the adverse events (AEs) or serious AEs were treatment-related.

Elevation in serum lactate at the time of febrile neutropenia (FN) in hemodynamically-stable patients with hematologic malignancies (HM) is associated with the development of septic shock within 48 hours.

BACKGROUND: Hospitalized patients who develop febrile neutropenia (FN) are treated empirically with antibiotics due to a high risk of developing septic shock. Currently, there is no method to predict which patients are at greatest risk. This study was designed to determine whether serum lactate, measured at the time of FN, is associated with the development of septic shock in hospitalized hematologic malignancy (HM) patients. RESULTS: Of the 547 patients enrolled, 46 (8.4%; 95% CI 6.2-10.9) developed septic shock. Baseline characteristics were similar between the groups. In univariate analysis, tachypnea (OR 5.9; 95% CI: 2.0-16.9, p = 0.001) and lactate (OR 18.4; 95% CI: 4.1-81.6, p < 0.001) were significantly associated with the development of septic shock. In multivariate analysis, lactate and tachypnea remained independently associated with the development of septic shock. By ROC analysis, lactate provided incremental prognostic value compared to vital signs alone. METHODS: Vital signs and lactate were measured during episodes of FN. The primary endpoint was the development of septic shock. Using a prospective, nested, case-control design, controls were matched on length of stay at the time of septic shock to achieve 80% power to detect an OR of >or=2.5. Using logistic regression, we evaluated the association of vital signs and lactate with the subsequent development of septic shock. CONCLUSIONS: In FN patients, measurement of lactate during FN adds significant prognostic information about the risk of developing septic shock. Routine measurement of lactate may help identify patients who may benefit from increased monitoring and early intervention strategies.