Pharmacokinetic and Pharmacodynamic Evaluation of Ravulizumab in Adults with Severe Coronavirus Disease 2019

Abstract

Introduction: Terminal complement amplification is hypothesized to be a key contributor to the clinical manifestations of severe coronavirus disease 2019 (COVID-19). Ravulizumab, a humanized monoclonal antibody that binds with high affinity to complement protein C5 and inhibits terminal complement activation, is being evaluated as a treatment for COVID-19-related severe pneumonia, acute lung injury, and acute respiratory distress syndrome in an ongoing phase 3 randomized controlled trial (ALXN1210-COV-305). To address the overactivation of terminal complement in severe COVID-19 compared to the diseases in which ravulizumab is currently approved, a modified dosing regimen was adopted. This analysis evaluates preliminary pharmacokinetic/pharmacodynamic data to confirm the modified dosing regimen.

Methods: Weight-based ravulizumab doses were administered on days 1, 5, 10, and 15. Serum levels of ravulizumab and free C5 were measured before and after administration of ravulizumab and any time on day 22. Free C5 levels < 0.5 μg/mL indicate complete C5 inhibition. The pharmacokinetic target was defined as ravulizumab concentrations at the end of the dosing interval > 175 μg/mL, the concentration above which C5 is completely inhibited.

Results: Twenty-two patients were included in this evaluation. At baseline, mean C5 concentration was 240 ± 67 μg/mL. In all patients and at all individual timepoints after the first dose was administered, ravulizumab concentrations remained > 175 μg/mL and free C5 concentrations remained < 0.5 μg/mL.

Conclusion: High levels of baseline C5 observed in patients with severe COVID-19 contribute to the growing body of evidence that suggests this disease is marked by amplification of terminal complement activation. Data from this preliminary pharmacokinetic/pharmacodynamic evaluation of 22 patients with severe COVID-19 show that the modified ravulizumab dosing regimen achieved immediate and complete terminal complement inhibition, which can be sustained for up to 22 days. These data support the continued use of this dosage regimen in the ongoing phase 3 study.

Trial registration: ClinicalTrials.gov identifier, NCT04369469.

Keywords: Antibodies; Complement C5/antagonists and inhibitors; Complement inactivating agents/therapeutic use; Coronavirus disease 2019; Humanized/therapeutic use; Monoclonal; Ravulizumab; Terminal complement pathway.

Fig. 1

Ravulizumab and free C5 concentrations over time. a Mean (± standard deviation) serum ravulizumab concentrations; b serum free C5 concentrations. Serum ravulizumab and free C5 concentrations were measured before and after ravulizumab was administered on study days 1, 5, 10, and 15, and any time on day 22. Complete terminal complement inhibition (PD threshold) was defined as serum free C5 levels < 0.5 μg/mL [20]. The PK threshold for maintaining complete terminal complement inhibition was defined as a serum ravulizumab concentration > 175 μg/mL [24]. ^an = 13 pre-dose; one patient withdrew after the day 10 pre-dose blood draw but prior to receiving the day 10 ravulizumab dose. In b, the top and the bottom of the box correspond to the 75th and 25th percentiles, respectively. The whiskers represent 1.5 times the interquartile range (75th percentile–25th percentile). PK pharmacokinetic, PD pharmacodynamic