Intramuscular AZD7442 (Tixagevimab-Cilgavimab) for Prevention of Covid-19

Abstract

Background: The monoclonal-antibody combination AZD7442 is composed of tixagevimab and cilgavimab, two neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that have an extended half-life and have been shown to have prophylactic and therapeutic effects in animal models. Pharmacokinetic data in humans indicate that AZD7442 has an extended half-life of approximately 90 days.

Methods: In an ongoing phase 3 trial, we enrolled adults (≥18 years of age) who had an increased risk of an inadequate response to vaccination against coronavirus disease 2019 (Covid-19), an increased risk of exposure to SARS-CoV-2, or both. Participants were randomly assigned in a 2:1 ratio to receive a single dose (two consecutive intramuscular injections, one containing tixagevimab and the other containing cilgavimab) of either 300 mg of AZD7442 or saline placebo, and they were followed for up to 183 days in the primary analysis. The primary safety end point was the incidence of adverse events after a single dose of AZD7442. The primary efficacy end point was symptomatic Covid-19 (SARS-CoV-2 infection confirmed by means of reverse-transcriptase-polymerase-chain-reaction assay) occurring after administration of AZD7442 or placebo and on or before day 183.

Results: A total of 5197 participants underwent randomization and received one dose of AZD7442 or placebo (3460 in the AZD7442 group and 1737 in the placebo group). The primary analysis was conducted after 30% of the participants had become aware of their randomized assignment. In total, 1221 of 3461 participants (35.3%) in the AZD7442 group and 593 of 1736 participants (34.2%) in the placebo group reported having at least one adverse event, most of which were mild or moderate in severity. Symptomatic Covid-19 occurred in 8 of 3441 participants (0.2%) in the AZD7442 group and in 17 of 1731 participants (1.0%) in the placebo group (relative risk reduction, 76.7%; 95% confidence interval [CI], 46.0 to 90.0; P<0.001); extended follow-up at a median of 6 months showed a relative risk reduction of 82.8% (95% CI, 65.8 to 91.4). Five cases of severe or critical Covid-19 and two Covid-19-related deaths occurred, all in the placebo group.

Conclusions: A single dose of AZD7442 had efficacy for the prevention of Covid-19, without evident safety concerns. (Funded by AstraZeneca and the U.S. government; PROVENT ClinicalTrials.gov number, NCT04625725.).

Figure 1. Relative Risk Reduction in the Incidence of the First SARS-CoV-2 RT-PCR–Positive Symptomatic Illness with AZD7442 as Compared with Placebo, at a Median 6-Month Follow-up.

Estimates are based on Poisson regression with robust variance with the use of a full model or reduced model. An estimated relative risk reduction greater than 0 favored AZD7442. Panel A shows the relative risk reduction according to the baseline demographic and clinical characteristics of the participants. The relative risk reduction with AZD7442 could not be estimated for participants of American Indian or Alaskan Native heritage or those with immunosuppressive disease or sickle cell disease, because there were no instances of SARS-CoV-2 RT-PCR–positive symptomatic illness in participants in those subgroups. Panel B shows the relative risk reduction according to the participants’ coexisting conditions. The body-mass index (BMI) is the weight in kilograms divided by the square of the height in meters. Immunosuppressive treatment is medication that suppresses the immune response, and immunosuppressive disease is a medical condition that could suppress the immune response, regardless of treatment. CI denotes confidence interval, COPD chronic obstructive pulmonary disease, Covid-19 coronavirus disease 2019, NE not estimable, RT-PCR reverse-transcriptase–polymerase chain reaction, and SARS-CoV-2 severe acute respiratory syndrome coronavirus 2.

Figure 2. Time to First SARS-CoV-2 RT-PCR–Positive Symptomatic Illness.

Shown are Kaplan–Meier curves from a time-to-event analysis of the proportion of participants in the full preexposure analysis set who had a first SARS-CoV-2 RT-PCR–positive symptomatic illness, with a median follow-up of 6 months. The hazard ratio and corresponding 95% confidence interval were obtained from a Cox proportional-hazards model with the group as a covariate and with the stratification factor of age at informed consent (≥60 years or <60 years). Tick marks indicate censored data. The inset shows the same data on an enlarged y axis.