Clinical efficacy of different monoclonal antibody regimens among non-hospitalised patients with mild to moderate COVID-19 at high risk for disease progression: a prospective cohort study

Abstract

This study aimed to compare the clinical progression of COVID-19 in high-risk outpatients treated with the monoclonal antibodies (mAb) bamlanivimab, bamlanivimab-etesevimab and casirivimab-imdevimab. This is an observational, multi-centre, prospective study conducted from 18 March to 15 July 2021 in eight Italian tertiary-care hospitals including mild-to-moderate COVID-19 outpatients receiving bamlanivimab (700 mg), bamlanivimab-etesevimab (700-1400 mg) or casirivimab-imdevimab (1200-1200 mg). All patients were at high risk of COVID-19 progression according to Italian Medicines Agency definitions. In a patient subgroup, SARS-CoV-2 variant and anti-SARS-CoV-2 serology were analysed at baseline. Factors associated with 28-day all-cause hospitalisation were identified using multivariable multilevel logistic regression (MMLR) and summarised with adjusted odds ratio (aOR) and 95% confidence interval (CI). A total of 635 outpatients received mAb: 161 (25.4%) bamlanivimab, 396 (62.4%) bamlanivimab-etesevimab and 78 (12.2%) casirivimab-imdevimab. Ninety-five (15%) patients received full or partial SARS-CoV-2 vaccination. The B.1.1.7 (Alpha) variant was detected in 99% of patients. Baseline serology showed no significant differences among the three mAb regimen groups. Twenty-eight-day all-cause hospitalisation was 11.3%, with a significantly higher proportion (p 0.001) in the bamlanivimab group (18.6%), compared to the bamlanivimab-etesevimab (10.1%) and casirivimab-imdevimab (2.6%) groups. On MMLR, aORs for 28-day all-cause hospitalisation were significantly lower in patients receiving bamlanivimab-etesevimab (aOR 0.51, 95% CI 0.30-0.88 p 0.015) and casirivimab-imdevimab (aOR 0.14, 95% CI 0.03-0.61, p 0.009) compared to those receiving bamlanivimab. No patients with a history of vaccination were hospitalised. The study suggests differences in clinical outcomes among the first available mAb regimens for treating high-risk COVID-19 outpatients. Randomised trials are needed to compare efficacy of mAb combination regimens in high-risk populations and according to circulating variants.

Keywords: Bamlanivimab-etesevimab, casirivimab-imdevimab; Mild-to-moderate COVID-19 outpatients; Monoclonal antibody treatments for COVID-19; SARS-CoV-2 early treatments.

Fig. 1

Plots of marginal predicted probabilities of 28-day all-cause hospitalisation by age and mAb regimen

Fig. 2

Serology in a sub-selection of patients receiving mAb therapy. a Anti-nucleocapsid, anti-RBD and anti-spike measurement in patients prior to the administration of mAb therapy to study baseline anti-SARS-CoV-2 immunity. Serum samples from the bamlanivimab (n = 44), bamlanivimab/etesevimab (n = 108) and casirivimab/imdevimab (n = 17) collected prior to mAb administration were measured at 1:1000 dilution. Low, mid and high lines indicate the SARS-CoV-2 WHO standards. b Natural immunity assessment after day 7 and day 28 of mAb treatment. Anti-nucleocapsid measurements at day 7 (bamlanivimab n = 21; bamlanivimab-etesevimab, n = 29; and casirivimab-imdevimab, n = 16) and day 28 (bamlanivimab/etesevimab, n = 67; casirivimab/imdevimab, n = 5) were compared with anti-nucleocapsid titres at the timepoint before infusion. c Synthetic mAb stability studied with anti-spike and anti-RBD measurements at day 7 and day 28 after mAb treatment on samples enumerated in b. Box plots indicate median (middle line), 25th and 75th percentiles (box) and 5th and 95th percentiles (whiskers) as well as outliers. ***p < 0.001. **p < 0.010. *p < 0.050. ns: non-significant

Fig. 3

Seroneutralization in a sub-selection of patients receiving mAb therapy. Anti-RBD, Ant-Spike (WT, Wuhan) and Anti-Spike (B.1.1.7/alpha) measurements in patients treated with bamlanivimab (n = 41 (D2) and n = 35 (T2), bamlanivimab-etesevimab (n = 97 (D2), n = 91 (D7), n = 67 (D28)) and casirivimab-imdevimab (n = 17 (D2), n = 16 (D7), n = 5 (D28). (D) Neutralizing antibody measurements against 10 different SARS-CoV-2 variants of concern (VOCs). Box plots indicate median (middle line), 25th and 75th percentiles (box), and 5th and 95th percentiles (whiskers). ***p < 0.001. **p < 0.010. *p < 0.050. ns: non-significant