Efficacy, safety, pharmacokinetics, immunogenicity, and serum neutralizing activity of AZD7442 (tixagevimab-cilgavimab) in patients hospitalized with COVID-19: long-term results from the DisCoVeRy trial.
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Massonnaud Clément R, Peiffer-Smadja Nathan, Poignard Pascal, Jamard Simon, Goehringer François, Danion François, Reignier Jean, de Castro Nathalie, Garot Denis, Lapique Eva Larranaga, Lacombe Karine, Tolsma Violaine, Faure Emmanuel, Malvy Denis, Staub Thérèse, Courjon Johan, Cazenave-Roblot France, Dyrhol Riise Anne Ma, Leturnier Paul, Martin-Blondel Guillaume, Roger Claire, Akinosoglou Karolina, Le Moing Vincent, Piroth Lionel, Sellier Pierre, Lescure Xavier, Trøseid Marius, Clevenbergh Philippe, Dalgard Olav, Gallien Sébastien, Gousseff Marie, Loubet Paul, Vardon-Bounes Fanny, Visée Clotilde, Belkhir Leila, Botelho-Nevers Élisabeth, Cabié André, Kotanidou Anastasia, Lanternier Fanny, Rouveix-Nordon Elisabeth, Silva Susana, Thiery Guillaume, Carcelain Guislaine, Diallo Alpha, Mercier Noémie, Terzić Vida, Bouscambert-Duchamp Maude, Gaymard Alexandre, Destras Grégory, Josset Laurence, Belhadi Drifa, Billard Nicolas, Guedj Jérémie, Han Thi-Hong-Lien, Couffin-Cadiergues Sandrine, Dechanet Aline, Delmas Christelle, Esperou Hélène, Fougerou-Leurent Claire, Le Mestre Soizic, Métois Annabelle, Noret Marion, Bally Isabelle, Dergan-Dylon Sebastián, Tubiana Sarah, Kalif Ouifiya, Bergaud Nathalie, Leveau Benjamin, Eustace Joe, Greil Richard, Hajdu Edit, Halanova Monika, Paiva Jose-Artur, Piekarska Anna, Baño Jesus Rodriguez, Tonby Kristian, Trojánek Milan, Tsiodras Sotirios, Unal Serhat, Burdet Charles, Costagliola Dominique, Yazdanpanah Yazdan, Mentré France, Ader Florence, Hites Maya, DisCoVeRy study group
Аннотация
METHODS: In this phase 3, double-blind, randomized, multicentre trial, hospitalized adults with PCR-confirmed SARS-CoV-2 infection were randomly assigned 1:1 to receive AZD7442 or placebo, and followed-up until day 456, with repeated blood sample collections until day 365. Clinical endpoints included clinical status, mortality, rehospitalization, SARS-CoV-2 reinfection, and adverse events. Antidrug antibodies and serum drug concentrations were measured. Analyses were performed on the modified intention-to-treat (mITT) populations, defined as participants who actually received the intervention.
RESULTS: Between April 28, 2021, and June 23, 2022, 237 participants were randomly assigned to AZD7442 (n = 127) or placebo (n = 110), and 123 participants actually received AZD7442. Participants were infected with pre-Omicron variants in 58.8% (133/226) of cases, versus 33.2% (75/226) of Omicron BA1, BA2, or BA5, and 8% (18/226) missing data. There was no significant difference in the distribution of the 7-point ordinal scale between the AZD7442 and placebo groups, either on day 15 (primary endpoint) (OR = 0.93 [0.54-1.61], p 0.81), or any other time point. Significantly more rehospitalizations occurred between discharge and day 456 among participants who received AZD7442 in the global mITT population (OR = 2.04 [1.03-4.05], p 0.04), but not in the antigen-positive mITT population (OR = 1.78 [0.80-3.94], p 0.15). No significant differences were observed in mortality, SARS-CoV-2 reinfection, or adverse events. In the AZD7442 group, 12 of 87 participants (13.8%) had treatment-emergent antidrug antibodies versus 5 of 69 (7.2%) in the placebo group (OR = 2.02 [0.66-6.14], p 0.21). Serum drug concentrations were detectable up to day 365 for all sampled participants (35/35). Neutralizing antibody titres were significantly higher in the AZD7442 group up to day 180.
CONCLUSIONS: AZD7442 did not demonstrate any clinical benefit and was safe up to 15 months. This study also provides valuable data on the pharmacokinetics, immunogenicity, and neutralizing activity of AZD7442 in patients hospitalized with COVID-19.