Efficacy, safety, pharmacokinetics, immunogenicity, and serum neutralizing activity of AZD7442 (tixagevimabcilgavimab) in hospitalized COVID-19 patients: long-term results from the DisCoVeRy trial

Objectives. To report long-term clinical efficacy, safety, pharmacokinetics, immunogenicity and seroneutralization results of AZD7442 (monoclonal antibodies tixagevimab-cilgavimab) in hospitalized COVID-19 patients. Methods. In this phase 3, double-blind, randomized, multicenter trial, hospitalized adults with PCR-confirmed SARS-CoV-2 infection were randomized 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 (ADA) and serum drug concentrations were measured. Analyses were performed on the modified intention-to-treat populations, defined as participants who actually received the intervention. Results. Between April 28, 2021, and June 23, 2022, 237 participants were randomized 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 Page 7 of 92 Clinical Microbiology and Infection 123456789 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review 6 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, 12/87 participants (13.8%) had treatment-emergent ADA versus 5/69 (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 hospitalized COVID-19 patients.