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Clinical Trial
. 2023 May 12;227(10):1153-1163.
doi: 10.1093/infdis/jiad014.

Safety, Tolerability and Pharmacokinetics of Half-Life Extended Severe Acute Respiratory Syndrome Coronavirus 2 Neutralizing Monoclonal Antibodies AZD7442 (Tixagevimab-Cilgavimab) in Healthy Adults

Pablo Forte-Soto  1 , Muna Albayaty  1   2 , Dennis Brooks  3 , Rosalinda H Arends  4 , John Tillinghast  5 , Anastasia A Aksyuk  6 , Jerome Bouquet  7 , Cecil Chen  7 , Asfiha Gebre  4 , Robert J Kubiak  4 , Venkatesh Pilla Reddy  8 , Seth Seegobin  9 , Katie Streicher  6 , Alison Templeton  9 , Mark T Esser  10
Affiliations
Clinical Trial

Safety, Tolerability and Pharmacokinetics of Half-Life Extended Severe Acute Respiratory Syndrome Coronavirus 2 Neutralizing Monoclonal Antibodies AZD7442 (Tixagevimab-Cilgavimab) in Healthy Adults

Pablo Forte-Soto et al. J Infect Dis. .

Abstract

Background: AZD7442 is a combination of extended half-life, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific neutralizing monoclonal antibodies (tixagevimab and cilgavimab).

Methods: This phase 1, first-in-human, randomized, double-blind, placebo-controlled, dose-escalation study evaluated AZD7442 administered intramuscularly (300 mg) or intravenously (300, 1000, or 3000 mg) in healthy adults (aged 18-55 years). The primary end point was safety and tolerability. Secondary end points included pharmacokinetics and antidrug antibodies.

Results: Between 18 August and 16 October 2020, a total of 60 participants were enrolled; 50 received AZD7442, and 10 received placebo. Adverse events (all of mild or moderate intensity) occurred in 26 participants (52.0%) in the AZD7442 groups and 8 (80.0%) in the placebo group. No infusion or injection site or hypersensitivity reactions occurred. Tixagevimab and cilgavimab had mean half-lives of approximately 90 days (range, 87.0-95.3 days for tixagevimab and 79.8--91.1 days for cilgavimab) and similar pharmacokinetic profiles over the 361-day study period. SARS-CoV-2-specific neutralizing antibody titers provided by AZD7442 were maintained above those in plasma from convalescent patients with coronavirus disease 2019 (COVID-19).

Conclusions: AZD7442 was well tolerated in healthy adults, showing a favorable safety profile across all doses. Depending on the SARS-CoV-2 variant, pharmacokinetic analyses suggest the AZD7442 could offer protection for ≥6 months against symptomatic COVID-19 after a single 300-mg intramuscular administration.

Clinical trials registration: NCT04507256.

Keywords: COVID-19; SARS-CoV-2; monoclonal antibody; pharmacokinetics; phase 1; safety; tolerability.

Plain language summary

Antibodies are proteins produced by the body in response to infections caused by microbes, including viruses. AZD7442 is a combination of 2 human antibodies, with an extended duration of effect, sourced from people who had recovered from coronavirus disease 2019 (COVID-19). These antibodies recognize a specific part (spike protein) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, and prevent the virus from infecting cells in the body. The current study evaluated the safety of AZD7442 in healthy volunteers. Sixty adults were given AZD7442 or placebo (salt solution) as injections into the muscle (300-mg dose) or infusions into a vein (300–3000-mg doses). The study did not find any safety issues with AZD7442, including at the highest dose. AZD7442 was measured in the blood 12 months after dosing, suggesting a long duration of protection. Following this study, AZD7442 was tested in larger clinical trials to investigate its potential in preventing and treating COVID-19. AZD7442 is currently authorized as treatment for outpatients with COVID-19 and as a preventive drug in people who may not respond well to COVID-19 vaccines and need additional protection (eg, those taking medications that dampen the immune system).

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Conflict of interest statement

Potential conflicts of interest. P. F. S. is an employee of Parexel International and does not hold stock in AstraZeneca. M. A., D. B., R. H. A., J. T., A. A. A., J. B., C. C., A. G., R. J. K., V. P. R., S. S., K. S., A. T., and M. T. E. were employees of, and hold or may have held stock in, AstraZeneca at the time of study. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.
Figure 1.
Geometric mean (± geometric standard deviation) serum concentrations of tixagevimab, cilgavimab, and AZD7442 (tixagevimab + cilgavimab) after single-dose intramuscular or intravenous administration to healthy adults (pharmacokinetic analysis set). Abbreviation: coadmin, coadministered; seq, sequential.
Figure 2.
Figure 2.
Geometric mean (± geometric standard deviation) concentrations of tixagevimab, cilgavimab, and AZD7442 (tixagevimab + cilgavimab) in NLF after a single AZD7442 dose (pharmacokinetic analysis set). Abbreviations: coadmin, coadministered; NLF, nasal lining fluid; seq, sequentially administered.
Figure 3.
Figure 3.
Geometric mean (95% CI) neutralizing antibody titers against SARS-CoV-2 after single-dose intramuscular or intravenous administration of AZD7442 (tixagevimab + cilgavimab) to healthy adults compared with convalescent plasma (safety analysis set). Serum samples were from participants in the safety analysis set (all participants). Dashed line represents the GMT ± 95% CIs measured in convalescent plasma from patients with COVID-19 (GMT, 30.8; n = 28) [16]; error bars represent 95% CIs. Abbreviations: CI, confidence interval; coadmin, coadministered; COVID-19, coronavirus disease 2019; GMT, geometric mean titer; PRNT80, 80% plaque reduction neutralization titer; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; seq, sequentially administered.
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