Detailed results from the TACKLE Phase III outpatient treatment trial showed AstraZeneca's Evusheld (tixagevimab and cilgavimab, formerly AZD7442) provided clinically and statistically significant protection against progression to severe COVID-19 or death from any cause compared to placebo, with treatment with Evusheld earlier in the disease course leading to more favourable outcomes.[1] 

The data have been published in The Lancet Respiratory Medicine (https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(22)00180-1/fulltext).

TACKLE was conducted in non-hospitalised adults with mild-to-moderate COVID-19 who were symptomatic for seven days or less. In the trial, 90% of participants were at high risk of progression to severe COVID-19 due to co-morbidities or age.[1]

Hugh Montgomery, Professor of Intensive Care Medicine at University College London, UK and TACKLE principal investigator, said: "Despite the success of vaccines, many individuals such as older adults, individuals with co-morbidities and those who are immunocompromised, remain at risk for poor outcomes from severe COVID-19. Additional options are needed to prevent disease progression and reduce the burden on healthcare systems, especially with the continued emergence of new variants. The TACKLE results show that one intramuscular dose of Evusheld can prevent these individuals from progressing to severe COVID-19, with earlier treatment leading to even better results."

Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, AstraZeneca, said: "These results published in The Lancet Respiratory Medicine add to the growing evidence supporting the use of Evusheld to help patients who most need additional protection against COVID-19. We are discussing the TACKLE data with regulatory authorities and continue to progress submissions in both treatment and prophylaxis indications to help combat COVID-19 on all fronts."    

In TACKLE, a single 600mg intramuscular (IM) dose of Evusheld significantly reduced the relative risk of progressing to severe COVID-19 or death (from any cause) by 50% (95% confidence interval [CI] 15, 71; p=0.010) through day 29 compared to placebo in non-hospitalised patients with mild-to-moderate COVID-19 who were symptomatic for seven days or less, the trial's primary endpoint.

In pre-specified analyses of participants who received treatment within three days of symptom onset, Evusheld reduced the risk of developing severe COVID-19 or death (from any cause) by 88% compared to placebo (95% CI 9, 98), and the risk reduction was 67% (95% CI 31, 84) when participants received Evusheld within five days of symptom onset.[1]  

Evusheld also reduced the risk of respiratory failure, a secondary endpoint, by 72% (95% CI 0.3, 92; nominal p=0·036), with three Evusheld participants (0.7%) versus 11 placebo participants (3%) requiring measures such as mechanical ventilation or extracorporeal membrane oxygenation[1.]

Evusheld was generally well-tolerated in the trial. Adverse events (AEs) occurred more frequently in the placebo group than the Evusheld group, 36% and 29%, respectively. The most common AE was COVID-19 pneumonia, occurring in 49 participants (11%) in the placebo group and 26 participants (6%) in the Evusheld group. Serious AEs occurred in 12% of participants in the placebo group and 7% in the Evusheld group.[1 ]There were six COVID-19-reported deaths in the placebo group and three in the Evusheld group.[1]

TACKLE

TACKLE is a Phase III, randomised, double-blind, placebo-controlled, multi-centre trial assessing the safety and efficacy of a single 600mg IM dose of Evusheld compared to placebo for the outpatient treatment of mild-to-moderate COVID-19. The trial was conducted in 95 sites in the US, Latin America, Europe and Japan. 903 participants were randomised (1:1) to receive either Evusheld (n = 452) or saline placebo (n = 451), administered in two separate, sequential IM injections.

Participants were adults 18 years-old and over who had mild-to-moderate COVID-19, were symptomatic for seven days or less and were not hospitalised. Participants had a documented laboratory-confirmed SARS-CoV-2 infection, as determined by a molecular test (antigen or nucleic acid) from any respiratory tract specimen (e.g. oropharyngeal, nasopharyngeal, or nasal swab or saliva) collected no more than three days prior to day 1.  Participants were not vaccinated against COVID-19 at the time of screening.

The primary efficacy endpoint was the composite of either severe COVID-19 or death from any cause through day 29. Subjects will continue to be followed for 15 months.

Approximately 13% of participants were 65 years and over. In addition, 90% had baseline co-morbidities and other characteristics that put them at high risk of progression to severe COVID-19, including cancer, diabetes, obesity, chronic lung disease or asthma, cardiovascular disease or immunosuppression. Approximately 62% were White/Caucasian, 4% Black/African American, 6% Asian and 24% American Indian or Alaskan Native. Approximately 52% of participants were Hispanic/Latino.

AstraZeneca previously announced (https://www.astrazeneca.com/media-centre/press-releases/2021/azd7442-phiii-trial-positive-in-covid-outpatients.html) positive high-level results from the TACKLE Phase III trial in the treatment of mild-to-moderate COVID-19.

Evusheld

Evusheld, formerly known as AZD7442, is a combination of two long-acting antibodies - tixagevimab (AZD8895) and cilgavimab (AZD1061) - derived from B-cells donated by individuals previously infected with the SARS-CoV-2 virus. Discovered by Vanderbilt University Medical Center and licensed to AstraZeneca in June 2020 (https://www.astrazeneca.com/media-centre/articles/2020/advancing-our-discovery-of-novel-coronavirus-neutralising-antibodies-against-covid-19.html), the human monoclonal antibodies bind to distinct sites on the SARS-CoV-2 spike protein[2] and were optimised by AstraZeneca with half-life extension and reduced Fc receptor and complement C1q binding.[3 ]The half-life extension more than triples the durability of its action compared to conventional antibodies;[4-6] data from the Phase III PROVENT trial show protection lasting at least six months.[7 ]The reduced Fc receptor binding aims to minimise the risk of antibody-dependent enhancement of disease - a phenomenon in which virus-specific antibodies promote, rather than inhibit, infection and/or disease.[8]

There is a growing body of evidence from multiple independent in vitro and in vivo (animal model) studies supporting the potential of Evusheld to protect against Omicron SARS-CoV-2 subvariants and all tested variants of concern to date.[9-13] In particular, data from Washington University School of Medicine (https://www.astrazeneca.com/media-centre/medical-releases/evusheld-long-acting-antibody-combination-retains-neutralising-activity-against-omicron-variants-including-ba2-in-new-independent-studies.html#!) demonstrated Evusheld retained neutralising activity against the highly transmissible BA.2 subvariant, which is currently the dominant strain globally.[9,14] This study also showed that Evusheld reduced viral burden and limited inflammation in the lungs (in vivo) for Omicron BA.1, BA.1.1 and BA.2.[9]  A new preclinical study (https://www.biorxiv.org/content/10.1101/2022.05.21.492554v1) from the University of Oxford showed that Evusheld also retains neutralisation activity against the emerging Omicron BA.4 and BA.5 variants.[13]

Evusheld has marketing authorisation in the European Union and was granted conditional marketing authorisation by the Medicines and Healthcare products Regulatory Agency (MHRA) in Great Britain for pre-exposure prophylaxis of COVID-19. Evusheld is authorised for emergency use for pre-exposure prophylaxis of COVID-19 in the US. Evusheld is also authorised for use and being supplied in several other countries around the world. Regulatory filings are progressing in both prevention and treatment around the world.  

Evusheld is being developed with support from the US government, including federal funds from the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority in partnership with the Department of Defense; Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense, under Contract No. W911QY-21-9-0001.

Under the terms of the licensing agreement with Vanderbilt, AstraZeneca will pay single-digit royalties on future net sales.

AstraZeneca

AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialisation of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit astrazeneca.com (https://www.astrazeneca.com/media-centre/press-releases/2021/twitter.com/AstraZeneca) and follow the Company on Twitter @AstraZeneca (https://www.astrazeneca.com/media-centre/press-releases/2021/twitter.com/AstraZeneca).

Contacts

For details on how to contact the Investor Relations Team, please click here (https://www.astrazeneca.com/investor-relations.html#Contacts). For Media contacts, click here (https://www.astrazeneca.com/media-centre/contacts.html).

References

1.   Montgomery H, et al. Efficacy and Safety of Intramuscular Administration of AZD7442 (Tixagevimab/Cilgavimab) for Early Outpatient Treatment of COVID-19: The TACKLE Phase 3 Randomised Controlled Trial. Lancet Respir Med. Published online June 7, 2022. doi.org/10.1016/S2213-2600(22)00180-1

2.    Dong J, et al. Genetic and Structural Basis for SARS-CoV-2 Variant Neutralization by a Two-Antibody Cocktail. Nat Microbiol. 2021;6(10):1233-1244. doi:10.1038/s41564-021-00972-2

3.    Loo YM, et al. AZD7442 Demonstrates Prophylactic and Therapeutic Efficacy in Non-Human Primates and Extended Half-Life in Humans. Sci Transl Med. 2022;14(635):eabl8124

4.    Robbie GJ, et al. A Novel Investigational Fc-Modified Humanized Monoclonal Antibody, Motavizumab-YTE, Has an Extended Half-Life in Healthy Adults. Antimicrobial Agents and Chemotherapy. 2013;57(12):6147. doi:10.1128/AAC.01285-13

5.    Griffin MP, et al. Safety, Tolerability, and Pharmacokinetics of MEDI8897, the Respiratory Syncytial Virus Prefusion F-Targeting Monoclonal Antibody with an Extended Half-Life, in Healthy Adults. Antimicrob Agents Chemother. 2017;61(3)

6.    Domachowske JB, et al. Safety, Tolerability and Pharmacokinetics of MEDI8897, an Extended Half-Life Single-Dose Respiratory Syncytial Virus Prefusion F-Targeting Monoclonal Antibody Administered as a Single Dose to Healthy Preterm Infants. Pediatr Infect Dis J. 2018;37(9):886-892

7.    Levin MJ, et al. Intramuscular AZD7442 (Tixagevimab-Cilgavimab) for Prevention of Covid-19. New England Journal of Medicine. Published online April 20, 2022. doi:10.1056/NEJMoa2116620

8.    van Erp EA, et al. Fc-Mediated Antibody Effector Functions During Respiratory Syncytial Virus Infection and Disease. Front Immunol. 2019;10(MAR)

9.    Case JB, et al. Resilience of S309 and AZD7442 Monoclonal Antibody Treatments against Infection by SARS-CoV-2 Omicron Lineage Strains. bioRxiv. Published online March 18, 2022:2022.03.17.484787. doi:10.1101/2022.03.17.484787

10. VanBlargan LA, et al. An Infectious SARS-CoV-2 B.1.1.529 Omicron Virus Escapes Neutralization by Therapeutic Monoclonal Antibodies. Nature Medicine 2022. Published online January 19, 2022:1-6. doi:10.1038/s41591-021-01678-y

11. Dejnirattisai W, et al. SARS-CoV-2 Omicron-B.1.1.529 Leads to Widespread Escape from Neutralizing Antibody Responses. Cell. 2022;185(3):467-484.e15

12. US Food and Drug Administration FACT SHEET FOR HEALTHCARE PROVIDERS: EMERGENCY USE AUTHORIZATION FOR EVUSHELD[TM] (Tixagevimab Co-Packaged with Cilgavimab). Available at: https://www.fda.gov/media/154701/download [Last accessed: May 2022]

13. Tuekprakhon A, et al. Further Antibody Escape by Omicron BA.4 and BA.5 from Vaccine and BA.1 Serum. bioRxiv. Published online May 21, 2022. doi:https://doi.org/10.1101/2022.05.21.492554

14. World Health Organization. Weekly Epidemiological Update on COVID-19 - 25 May 2022. Available at: https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---25-may-2022 [Last accessed: May 2022]