Anti-SARS-CoV-2 glyco-humanized polyclonal antibody XAV-19: phase II/III randomized placebo-controlled trial shows acceleration to recovery for mild to moderate patients with COVID-19

Abstract

Introduction: XAV-19 is a glyco-humanized swine polyclonal antibody targeting SARS-CoV-2 with high neutralizing activity. The safety and clinical efficacy of XAV-19 were investigated in patients with mild to moderate COVID-19.

Methods: This phase II/III, multicentric, randomized, double-blind, placebo-controlled clinical trial was conducted to evaluate the safety and clinical efficacy of XAV-19 in patients with a seven-point WHO score of 2 to 4 at randomization, i.e., inpatients with COVID-19 requiring or not requiring low-flow oxygen therapy, and outpatients not requiring oxygen (EUROXAV trial, NCT04928430). Adult patients presenting in specialized or emergency units with confirmed COVID-19 and giving their consent to participate in the study were randomized to receive 150 mg of XAV-19 or placebo. The primary endpoint was the proportion of patients with aggravation within 8 days after treatment, defined as a worsening of the seven-point WHO score of at least one point between day 8 and day 1 (inclusion). The neutralization activity of XAV-19 against variants circulating during the trial was tested in parallel.

Results: From March 2021 to October 2022, 279 patients received either XAV-19 (N = 140) or placebo (N = 139). A slow enrollment and a low rate of events forced the termination of the premature trial. XAV-19 was well tolerated. Underpowered statistics did not allow the detection of any difference in the primary endpoint between the two groups or in stratified groups. Interestingly, analysis of the time to improvement (secondary endpoint) showed that XAV-19 significantly accelerated the recovery for patients with a WHO score of 2 or 3 (median at 7 days vs. 14 days, p = 0.0159), and even more for patients with a WHO score of 2 (4 days vs. 14 days, p = 0.0003). The neutralizing activity against Omicron and BA.2, BA.2.12.1, BA.4/5, and BQ.1.1 subvariants was shown.

Discussion: In this randomized placebo- controlled trial with premature termination, reduction of aggravation by XAV-19 at day 8 in patients with COVID-19 was not detectable. However, a significant reduction of the time to improvement for patients not requiring oxygen was observed. XAV-19 maintained a neutralizing activity against SARS-CoV-2 variants. Altogether, these data support a possible therapeutic interest for patients with mild to moderate COVID-19 requiring anti-SARS-CoV-2 neutralizing antibodies.

Clinical trial registration: https://clinicaltrials.gov/, identifier NCT04928430; https://www.clinicaltrialsregister.eu/about.html (EudraCT), identifier 2020-005979-12.

Keywords: (glyco-humanized) polyclonal antibody; COVID-19; SARS-CoV-2 variants; XAV-19; clinical trial.

Figure 1

Flow of participants in the EUROXAV phase II/III clinical trial, an international, placebo-controlled, double-blind, randomized clinical trial to evaluate the efficacy and safety of 150 mg of XAV-19 infusion, in patients with mild to moderate COVID-19.

Figure 2

Time to clinical improvement. Kaplan–Meier curves by randomization group on the whole TARGET population (A) or on the TARGET population with a score of 2, 2 to 3, 3 to 4, or 4 at baseline (B). Improvement was defined as a diminution of at least one point on the WHO score compared to the WHO score at day 1. Dotted lines represent the median time to improvement.

Figure 3

XAV-19 antiviral activity against Omicron and its subvariants. (A) Binding of XAV-19 or Evusheld to Wuhan or Omicron and its subvariant RBD: XAV-19 or Evusheld was added to RBD-coated plates at the indicated concentration and revealed with an HRP-conjugated secondary anti-pig or anti-human antibody. (B) Neutralizing activity of XAV-19 or Evusheld to Wuhan or Omicron and its subvariant RBD: recombinant His-Tag-RBD pre-incubated with XAV-19 or Evusheld was added to human ACE2-coated plates. Bound RBD was then detected with HRP-conjugated anti-His-Tag antibody. (C) Neutralizing activity of XAV-19 on whole replicating viruses: Vero E6 cells were infected with Wuhan or Omicron SARS-CoV-2 strains. CPE was assessed by microscopy examination and viral load percentage was determined by quantitative RT-PCR.

Figure 4

XAV-19 target epitopes lie outside the Omicron mutation sites. Amino acid sequence of the SARS-CoV-2 spike RBD variant Omicron and XAV-19 target epitopes (amino acid sequence numbered according to DBSOURCE sequence reference NC_045512.2). Bold: XAV-19 target epitopes confirmed by proteolytic epitope mapping; blue: amino acids in contact with ACE-2; yellow: mutations found in Omicron, differentiating from the original Wuhan RBD; underlined: tixagevimab/cilgavimab target epitopes.