Complement blockade with eculizumab for treatment of severe Coronavirus Disease 2019 in pregnancy: A case series

Abstract

Problem: We evaluated eculizumab, a complement protein C5 inhibitor, for treatment of severe COVID-19 in pregnant and postpartum individuals.

Method of study: Protocol ECU-COV-401 (clinicaltrials.gov NCT04355494) is an open label, multicenter, Expanded Access Program (EAP), evaluating eculizumab for treatment of severe COVID-19. Participants enrolled at our center from August 2020 to February 2021. Hospitalized patients were eligible if they had severe COVID-19 with bilateral pulmonary infiltrates and oxygen requirement. Eculizumab was administered on day 1 (1200 mg IV) with additional doses if still hospitalized (1200 mg IV on Days 4 and 8; 900 mg IV on Days 15 and 22; optional doses on Days 12 and 18). The primary outcome was survival at Day 15. Secondary outcomes included survival at Day 29, need for mechanical ventilation, and duration of hospital stay. We evaluated pharmacokinetic and pharmacodynamic data, safety, and adverse outcomes.

Results: Eight participants were enrolled at the Cedars-Sinai Medical Center, six during pregnancy (mean 30 ± 4.0 weeks) and two in the postpartum period. Baseline oxygen requirement ranged from 2 L/min nasal cannula to 12 L/min by non-rebreather mask. The median number of doses of eculizumab was 2 (range 1-3); the median time to hospital discharge was 5.5 days (range 3-12). All participants met the primary outcome of survival at Day 15, and all were alive and free of mechanical ventilation at Day 29. In three participants we demonstrated that free C5 and soluble C5b-9 levels decreased following treatment. There were no serious adverse maternal or neonatal events attributed to eculizumab at 3 months.

Conclusion: We describe use of eculizumab to treat severe COVID-19 in a small series of pregnant and postpartum adults. A larger, controlled study in pregnancy is indicated.

Keywords: COVID-19; complement system proteins; eculizumab; pregnancy.

Conflict of interest statement

R.M.B has received honorarium from Alexion Pharmaceuticals Inc (Alexion) for participation in speaker bureaus and advisory boards. J.W. III has participated in advisory boards and received honoraria from Natera Inc. S.K. is an employee of Alexion, AstraZeneca (AZ) Rare Disease, owns unvested AZ stock, and has a patent submitted for Complement inhibition in COVID‐19. D.D. is an employee of Alexion, AZ Rare Disease and owns AZ stock options and RSUs. M.M. is an employee of Alexion, AZ Rare Disease, owns AZ stock/RSUs, and has patents with Alexion unrelated to the current manuscript. S.M. is an employee of Alexion, AZ Rare Disease and owns AZ RSUs. J.M. is an employee of Alexion, AZ Rare Disease, owns unvested AZ stock, and has patents with Alexion. S.O. is an employee of Alexion, AZ Rare Disease, owns AZ stock/RSUs and patents with Alexion unrelated to the current manuscript. S.G. has received a grant/contract from IBSA pharmaceutical. The remaining authors report no disclosures.

© 2022 The Authors. American Journal of Reproductive Immunology published by John Wiley & Sons Ltd.

Figures

FIGURE 1

Study flow diagram among pregnant and postpartum participants. Ecu, eculizumab

FIGURE 2

Laboratory trends following treatment with eculizumab. (A) CRP; (B) Absolute lymphocyte count. Data are median (range); CRP, C‐reactive protein; Days represent study day, with the first dose of eculizumab on Day 1 and the second dose on Day 2 per protocol. The number of study participants with laboratory data on each day are provided on the table below each plot. Laboratory data on Days 1 and 4 are pre‐treatment values. Normal range: absolute lymphocyte count (1.0–4.5 × 109/L); C‐reactive protein (p = .02) and Day 5 versus Day 1 (p = .005); Absolute lymphocyte count, Day 5 versus Day 1 (p = .01)