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. 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 (NCT04723394). We report a post hoc analysis of the impact of AZD7442 in reducing self-reported COVID-19 symptom severity and time to symptom resolution through Day 29 in TACKLE. 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 600mg AZD7442 dose (2 consecutive intramuscular (IM) injections, 300 mg of each antibody;n=452) or placebo (n=451). Symptom occurrence and severity were self reported daily by participants through study Day 29. Participants rated each symptom as not experienced, mild, moderate, severe, or emergency room (ER) or hospital visit. Symptom progression was compared between AZD7442 and placebo using a stratified Cochran-Mantel-Haenszel test. Change from baseline in symptom severity was compared using a mixed model for repeated measures. Time to symptom resolution was compared using Kaplan-Meier and Cox proportional hazards methods. Missing symptom data for those who were hospitalized or died were imputed as either failures or as severity scores of ER or hospital visit. Results. Progression of >=1 symptoms to a worse severity score occurred in 170 (55.7%) AZD7442- versus 204 (63.4%) placebo-treated participants, translating to a nominally significant relative risk reduction of 12.5% (95% confidence interval 0.5- 23.0;P=0.041). Over 29 days, the overall mean improvement from baseline in severity of body aches, chills, cough, diarrhea, fatigue, headache, muscle aches, nausea, and runny nose was significantly greater with AZD7442 versus placebo (Figure). The greatest improvements were observed with cough, fatigue, and muscle aches. Significant differences were observed for most symptoms within 1 and 2 weeks post AZD7442 dosing. Figure. Forest plot for LS difference in severity of COVID-19 symptoms between AZD7442 and placebo through Day 29 CI, confidence interval;LS, least squares. The overall P value is calculated using a mixed model for repeated measures, including terms for symptom severity baseline value, time from symptom onset (<=5 vs >5 days), risk of progression to severe COVID-19 (high vs low), treatment, visit, and treatment by visit interaction. Conclusion. For the treatmentofmildtomoderateCOVID-19,a single IM600-mg AZD7442 dose was associated with reductions in progression of COVID-19 symptom severity and may hasten symptom improvement through Day 29.
ABSTRACT
Background. AZD7442 (tixagevimab/cilgavimab) is a combination of neutralizing monoclonal antibodies (mAbs) that bind to distinct epitopes on the SARS-CoV-2 spike protein, with neutralization activity against variants including Omicron. In the Phase 3 TACKLE study, AZD7442 significantly reduced severe disease progression or death and was well-tolerated through Day 29. Viral evolution during treatment has the potential for resistance selection, such as variants exhibiting reduced mAb binding. We report genotypic analysis and phenotypic characterization of variants identified over 15 days after AZD7442 treatment in TACKLE. Methods. In TACKLE (NCT04723394), non-hospitalized adults with mild to moderate COVID19 were randomized 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). Next-generation sequencing of the spike gene was performed on SARS-CoV-2 reverse-transcription polymerase chain reaction-positive nasal swabs (at baseline and Days 3, 6, and 15). SARS-CoV-2 lineages were assigned using spike nucleotide sequences. Amino acid substitutions, insertions, and deletions were analyzed at allele fractions (AF, % of sequence reads represented by mutation) >=25% and 3-25%. Results. Baseline spike sequences were available from 744 participants (82.4%) (AZD7442, n=380;placebo, n=364);87% of sequences corresponded to variants of concern/interest;these were balanced between AZD7442 and placebo groups (Table 1). Treatment-emergent (post-dosing) viral variants were rare, with 11 (4.5%) AZD7442 and 3 (1.3%) placebo participants showing the emergence of >=1 mutation at tixagevimab/cilgavimab binding sites, with an AF >=25% (Table 2). At AF 3- 25%, treatment-emergent viral variants in the AZD7442 binding site were observed in 16 (6.6%) AZD7442 and 15 (6.5%) placebo participants. Conclusion. Following AZD7442 treatment, low levels of SARS-CoV-2 variants bearing mutations at tixagevimab/cilgavimab binding sites were identified. These data indicate that combination of two antibodies creates a high genetic barrier for resistance, supporting the use of mAb combinations that bind to distinct epitopes for the treatment of COVID-19.