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.

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.

Efficacy and Safety of Adintrevimab (ADG20) for the Treatment of High-Risk Ambulatory Patients With Mild or Moderate Coronavirus Disease 2019: Results From a Phase 2/3, Randomized, Placebo-Controlled Trial (STAMP) Conducted During Delta Predominance and Early Emergence of Omicron.

Background: Safe and effective treatments are needed to prevent severe outcomes in individuals with coronavirus disease 2019 (COVID-19). We report results from STAMP, a phase 2/3, multicenter, double-blind, randomized, placebo-controlled trial of adintrevimab, an extended half-life monoclonal antibody, for treatment of high-risk ambulatory patients with mild to moderate COVID-19. Methods: Nonhospitalized, unvaccinated participants aged ≥12 years with mild to moderate COVID-19 and ≥1 risk factor for disease progression were randomized to receive a single intramuscular injection of 300 mg adintrevimab or placebo. Enrollment was paused due to the global emergence of the Omicron BA.1/BA1.1 variants, against which adintrevimab showed reduced activity in vitro. The primary efficacy endpoint was COVID-19-related hospitalization or all-cause death through day 29 in participants with COVID-19 due to laboratory-confirmed or suspected non-Omicron severe acute respiratory syndrome coronavirus 2 variants. Results: Between 8 August 2021 and 11 January 2022, 399 participants were randomized to receive adintrevimab (n = 198) or placebo (n = 201), including 336 with COVID-19 due to non-Omicron variants. COVID-19-related hospitalization or all-cause death through day 29 occurred in 8 of 169 (4.7%) participants in the adintrevimab group and 23 of 167 (13.8%) participants in the placebo group, a 66% relative risk reduction in favor of adintrevimab (standardized risk difference, -8.7% [95% confidence interval, -14.71% to -2.67%]; P = .0047). Incidence of treatment-emergent adverse events (TEAEs) was similar between treatment groups (33.9% for adintrevimab and 39.5% for placebo). No adintrevimab-related serious TEAEs were reported. Conclusions: Treatment with a single intramuscular injection of adintrevimab provided protection against severe outcomes in high-risk ambulatory participants with COVID-19 due to susceptible variants, without safety concerns. Clinical Trial Registration. NCT04805671.