Conestat alfa in the treatment of COVID-19

An exaggerated inflammatory reaction seems to be the main driver of Covid-19 progression up to and including lung failure. Conestat alfa is a man-made form of a protein that occurs naturally in the bloodstream and which blocks several of the inflammatory systems involved in Covid-19-related exaggerated inflammation. An animal study of the protein in coronavirus has already produced promising results.

The PROTECT-COVID-19 trial investigated whether Conestat alfa can prevent severe disease progression and the need for mechanical ventilation in hospitalized patients with Covid-19. In addition to efficacy and tolerability, the trial also assessed the level of inflammation in the two-week period following enrollment.

This international, multicenter, randomized, open-label trial enrolled 84 participants with moderate to severe Covid-19 in Switzerland, Brazil and Mexico starting in August 2020. Participants were randomized to treatment with Conestat alfa for 3 days in addition to standard of care or standard of care alone. Most patients received Dexamethasone as standard of care treatment, and Remdesivir was used occasionally. Conestat Alfa was well tolerated without any safety signal despite choosing a higher than licensed daily dosage. The trial was prematurely terminated in September 2021 following a preplanned second interim analysis demonstrating relevant baseline imbalances in the two treatment groups (e.g. disease severity was higher in the Conestat alfa group at baseline) and no differences in the primary and a key secondary endpoint. Consequently, the original aim to enroll 120 patients was deemed not to be sufficient to show a difference in the primary outcome measure given the imbalances observed at baseline. Further arguments to terminate the trial were the introduction of additional effective treatments such as monoclonal antibodies in the second half of 2021 and the fact that the analysis of inflammatory systems indicated that the chosen Conestat alfa treatment regimen was not able to significantly reduce inflammation compared to the control group.

Interventions that prevent Covid-19-induced lung failure play an important role in treating patients with the disease. Currently, Dexamethasone, Tocilizumab and Baricitinib have all shown to be effective in treating moderate to severe Covid-19 and preventing admission to the intensive care unit and mechanical ventilation. Results from this small study do not support the use of Conestat alfa in order to ameliorate the exaggerated inflammatory reaction and to prevent Covid-19 progression, although a larger trial would be desirable.

Recombinant human C1 esterase inhibitor (conestat alfa) in the prevention of critical SARS-CoV-2 infection in hospitalized patients with COVID-19: a randomized, parallel-group, openlabel, multi-center exploratory trial.