ABSTRACT
Background. Outpatient treatment with SARS-CoV-2-neutralizing antibody combination AZD7442 (tixagevimab/cilgavimab) in adults with mild to moderate COVID-19 significantly reduced progression to severe disease or death through Day 29 and was well-tolerated in the Phase 3 TACKLE study primary analysis (NCT04723394). AZD7442 administered earlier in the disease course leads to more favorable outcomes and has the potential to prevent COVID-19 hospitalizations and reduce hospital burden. We report key secondary efficacy results with longerterm safety data from TACKLE over 6 months. Methods. In TACKLE, non-hospitalized adults with mild to moderate COVID-19 were randomized 1:1 and dosed <=7 days from symptom onset with a single 600-mg AZD7442 dose (2 consecutive intramuscular injections, 300 mg of each antibody;n=452) or placebo (n=451). The key secondary endpoint was death from any cause or hospitalization for COVID-19 complications or sequelae through Day 169, analyzed using a Cochran-Mantel-Haenszel test stratified by time from symptom onset and risk of severe COVID-19 progression. Results. Death from any cause or hospitalization for COVID-19 complications or sequalae occurred in 20 (5.0%) versus 40 (9.8%) participants receiving AZD7442 versus placebo, respectively, translating to a relative risk reduction (RRR) of 49.1% (95% confidence interval [CI] 14.5-69.7) versus placebo (P=0.009). A sensitivity analysis excluding participants who were unblinded prior to Day 169 for consideration of vaccination yielded a similar RRR of 50.7% (95% CI 17.5-70.5;P=0.006). For baseline seronegative participants, an RRR of 58.6% (95% CI 27.6-76.4;P=0.001) was observed. The median (range) safety follow-up was 170 (1-330) days with AZD7442 and 170 (1-326) days with placebo. Adverse events occurred in 38.5% of AZD7442 participants and 43.5% of placebo participants, and were mostly mild to moderate. Conclusion. A single 600-mg AZD7442 dose demonstrated statistically significant protection against death from any cause or hospitalization for COVID-19 through 6 months, and was well-tolerated. These data provide further support of AZD7442 in the COVID-19 outpatient treatment setting, with potential to reduce hospital burden.
ABSTRACT
Background. Vaccines effectively prevent COVID-19, but some individuals have medical comorbidities or receive therapies that impair their immune response to vaccination, or are ineligible for vaccination. For such individuals who remain at risk of COVID-19, monoclonal antibodies may provide additional rapid protection. AZD7442 comprises 2 fully human extended half-life SARS-CoV-2-neutralizing antibodies that bind distinct epitopes of the viral spike protein receptor binding domain. AZD7442 is in development for the prevention and treatment of COVID-19. Here, we report primary Phase 3 study results of AZD7442 for pre-exposure prophylaxis of symptomatic COVID-19. Methods. PROVENT (NCT04625725) is a Phase 3, 2:1 randomized, double-blind, placebo-controlled study of a single 300-mg AZD7442 dose (2 intramuscular injections;150 mg each of tixagevimab and cilgavimab) for symptomatic COVID-19 prevention. Participants were unvaccinated adults (≥ 18 years old) without prior SARS-CoV-2 infection, who may benefit from immunoprophylaxis with antibodies due to an increased risk of either inadequate response to vaccination or SARS-CoV-2 exposure. The primary study endpoints were first case of SARS-CoV-2 RT-PCR-positive symptomatic illness post dose and prior to Day 183 (efficacy), and safety of AZD7442. Results. In total, 5197 participants (mean age 53.5 years, 46% female) were randomized and dosed (safety analysis set): AZD7442 n=3460;placebo n=1737. In the primary efficacy analysis (full pre-exposure analysis set, n=5172), AZD7442 reduced the risk of developing symptomatic COVID-19 by 77% (95% confidence interval 46.0, 90.0) vs placebo (P< 0.001) (Table). Adverse events occurred in 35% and 34% of participants administered AZD7442 and placebo, respectively, and injection site reactions occurred in 2.4% and 2.1% of participants, respectively (safety analysis set). There was 1 case of severe/critical COVID-19 and 2 COVID-19-related deaths in the placebo arm. Conclusion. The primary study endpoints were met: a one-time dose of AZD7442 demonstrated statistically significant protection against symptomatic COVID-19 and was well tolerated. AZD7442 is the first long-acting monoclonal antibody combination that represents a potential new option to augment COVID-19 prevention.