By Stan Deresinski, MD, FACP, FIDSA
Clinical Professor of Medicine, Stanford University
SYNOPSIS: The combination of tixagevimab and cilgavimab (Evusheld) was demonstrated to be effective in the prevention of symptomatic COVID-19, but much remains to be learned as SARS-CoV-2 continues to evolve.
SOURCE: Levin MJ, Ustianowski A, De Wit S, et al; PROVENT Study Group. Intramuscular AZD7442 (tixagevimab-cilgavimab) for prevention of Covid-19. N Engl J Med 2022; Apr 20. doi: 10.1056/NEJMoa2116620. [Online ahead of print].
Levin and colleagues reported the results of an ongoing randomized trial evaluating the efficacy of a combination of monoclonal antibodies (tixagevimab and cilgavimab, marketed as Evusheld) in the prevention of symptomatic COVID-19 in adults. Subjects were judged to be at risk, either because of a likely inadequate response to vaccination or increased risk of exposure due to location (e.g., nursing home) or circumstance. A total of 5,197 patients were randomized (2:1) to receive tixagevimab-cilgavimab, 300 mg of each component, as separate intramuscular injections at the same visit, or comparable placebo injections. The study took place between November 2020 and March 2021 (pre-Omicron).
Polymerase chain reaction (PCR)-confirmed symptomatic illness occurred in eight of 3,441 (0.2%) tixagevimab-cilgavimab recipients and 17 of 1,731 (1.0%) in those who received placebo through day 183. The relative risk reduction was 76.7% (95% confidence interval [CI], 46.0 to 90.0; P < 0.001). With extended follow-up at a median of six months, the relative risk reduction was 82.8%. In addition, there were five cases of severe or critical COVID-19 and two COVID-19-related deaths, and all seven occurred in the placebo group. Adverse events, mostly mild, occurred in approximately one-third of subjects in each group.
Genotyping was performed on isolates from a total of 20 patients, including from seven asymptomatic monoclonal recipients and 13 symptomatic placebo recipients and, among variants of concern, one was a beta (in a tixagevimab-cilgavimab subject) while there were five alpha subvariants and five delta among the placebo recipients.
Pharmacokinetic analysis revealed that serum neutralization titers 29 days after administration were 16-22 times higher than reported in convalescent plasma in individuals recovering from COVID-19, and significant serum levels were seen at six months.
COMMENTARY
Tixagevimab and cilgavimab each bind to distinct sites within the receptor biding domain of the SARS-CoV-2 spike protein. This allows continued activity of the combination if resistance to only one of the epitopes emerges. The emergence of the Omicron variant led to the discarding of two available monoclonal combinations, bamlanivimab/etesevimab and casirivimab/imdevimab, because of markedly reduced activity against the Omicron BA.1 and BA.2 variants, and sotrovimab because of more modestly reduced activity against BA.2.
The emergence of mutants capable of escaping monoclonal antibodies became of concern with regard to tixagevimab-cilgavimab when data indicated reduced activity of one of its components against BA.1. The combination of its components, however, retains significant in vitro activity against BA.2 — although BA.2 breakthrough infections have been identified. The reduced activity against BA.1 had led the U.S. Food and Drug Administration, in February 2022, to recommend a doubling of the doses of the components to 600 mg each, with the purpose of overcoming modest reductions in activity. This remains the currently used dose. Bebtelovimab, which has emergency use authorization for treatment but not prophylaxis, remains active against both BA.1 and BA.2.
Furthermore, with a half-life of 90 days, serum monoclonal antibody levels persisted after tixagevimab-cilgavimab administration for as long as nine months, with levels likely to be protective against susceptible variants for at least six months. The extended half-lives of the monoclonal components of tixagevimab-cilgavimab are the result of modifications that reduce binding to the Fc receptor and C1q. The issue of when repeat dosing is indicated already is being raised in the clinic, and the answer remains to be seen. This first depends on whether, in dealing with a constantly evolving virus, it remains efficacious when that time comes.
When tixagevimab-cilgavimab first received emergency use authorization, it was in very short supply and, as a consequence, its use primarily was directed at patients with significant immunocompromise, such as those who were transplant recipients. However, in the clinical trial results discussed here, there were only a total of 198 patients with immunocompromise, with symptomatic infection occurring in 1/125 and 2/93 tixagevimab-cilgavimab and placebo recipients, respectively. Thus, we really do not know the degree of benefit that may be achieved in these patients, just as we do not know for certain its efficacy in an Omicron world.
The combination of tixagevimab and cilgavimab (Evusheld) was demonstrated to be effective in the prevention of symptomatic COVID-19, but much remains to be learned as SARS-CoV-2 continues to evolve.
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