IL-1 is a key driver of inflammation in response to an initial trigger such as injury or infection, such as that caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In patients with COVID-19, progression from lower respiratory tract infection (LRTI) to severe respiratory failure (SRF) is dependent on the early release of IL-1α from infected lung epithelial cells, which in turn stimulates further cytokine production including IL-1β from alveolar macrophages.1
Progression to severe respiratory failure
In a subset of patients with COVID-19, an acute hyper-inflammatory response contributes to the development of severe pneumonia and respiratory failure. Blocking IL-1 signaling early may break the IL-1-driven, self-amplifying autoinflammatory loop, thus preventing escalation to hyperinflammation and progression to respiratory failure.1,2
Kineret was evaluated in a randomised, double-blind, placebo-controlled study in patients hospitalized with confirmed COVID-19 pneumonia and deemed to be at risk of developing SRF based on elevated levels of the inflammation biomarker soluble urokinase plasminogen activator receptor (suPAR). Treatment with Kineret was associated with a significant improvement in clinical status by day 28 compared with placebo (standard of care), as well as a higher number of patients making a full recovery and fewer patients progressing to SRF or death.3,4
The primary endpoint in the SAVE-MORE study was the comparative distribution of the frequencies of each score on the 11-point WHO CPS for Kineret plus SOC and SOC alone, respectively by day 28, expressed as odds ratio (OR) with 95% confidence intervals.
The unadjusted OR of 0.36 (95% CI 0.26-0.49; P<0.001) for the primary endpoint indicates a 64% improvement of the overall clinical status of patients treated with Kineret plus SOC by Day 28, compared with patients treated with SOC alone. In multivariate analysis, allocation to Kineret plus SOC or SOC alone was the only variable that was significantly associated with the final outcome (adjusted OR 0.36; 95%CI 0.26-0.50; P<0.0001).
Abbreviations
IL-1, interleukin 1; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; LRTI, lower respiratory tract infection; SRF, severe respiratory failure; suPAR, soluble urokinase plasminogen activator receptor; SOC, standard of care; WHO CPS, World Health Organization’s Clinical Progression Scale; OR, Overall response; PCR, positive polymerase chain reaction; NIV, non-invasive ventilation; HFO, high-flow oxygen; MV, mechanical ventilation; P/F, arterial partial pressure of oxygen (PaO2) divided by the inspired oxygen concentration (FiO2); ECMO, extracorporeal membrane oxygenation; CI, confidence interval.