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Update on FDA Adjustment to Evusheld Dosage Regimen in US

25 February 2022 -- The US Food and Drug Administration (FDA) has amended the Emergency Use Authorisation (EUA) Fact Sheet for AstraZeneca’s Evusheld (tixagevimab co-packaged with cilgavimab) for pre-exposure prophylaxis (prevention) of COVID-19 to reflect a change in the dosage regimen.

The revised authorised dosage regimen in the US is an initial dose of 300mg of tixagevimab and 300mg of cilgavimab, delivered in two consecutive, sequential intramuscular (IM) injections. The previous dosage regimen was 150mg IM each of tixagevimab and cilgavimab. The change was based on the Agency’s modelled assessment of Evusheld’s in vitro neutralising activity against the Omicron BA.1 and BA.1.1 (BA.1+R346K) subvariants currently circulating in the US.

New preclinical pseudovirus and authentic ‘live’ data included in the FDA Fact Sheet show that Evusheld neutralises BA.1.1 with decreased activity.1 Preclinical data from several independent studies, including previous data from the FDA and data from Washington University published in Nature, have demonstrated that Evusheld retains neutralising activity against the original Omicron BA.1 variant.2-4 In vitro activity does not always correlate with clinical efficacy. BA.1 and BA.1.1 currently represent 95% of sequenced COVID-19 cases in the US (February, 2022).5 Outside of the US, BA.1.1 currently represents a minority of Omicron BA.1 sequences reported.6

Additional new preclinical pseudovirus and authentic ‘live’ virus data included in the FDA Fact Sheet show that Evusheld retained neutralising activity against the emerging BA.2 variant with minimal impact.1 According to the World Health Organization, cases of BA.2 have been identified in 85 countries to date.7 Prevalence of BA.2 compared to BA.1 is increasing rapidly, with BA.2 now the dominant strain in several countries.6 In addition, a recent study found that BA.2 is substantially more transmissible than BA.1 and possesses immune-evasive properties that further reduce the protective effect of vaccination against infection.8

The update provides US healthcare providers with information to inform their use of Evusheld in light of the current circulating variants. The Company is working with health authorities and collecting clinical, real-world and laboratory data to continually monitor this dynamic environment, including the growing global prevalence of the BA.2 subvariant.

Evusheld is the only antibody therapy authorised in the US for pre-exposure prophylaxis of COVID-19.

Evusheld, a long-acting antibody combination, was authorised for emergency use in the US on 8 December, 2021 for pre-exposure prophylaxis (prevention) of COVID-19 in adults and adolescents (aged 12 and older who weigh 40kg or more) with moderate to severe immune compromise due to a medical condition or immunosuppressive medications and who may not mount an adequate immune response to COVID-19 vaccination, as well as those individuals for whom COVID-19 vaccination is not recommended due to a history of severe adverse reaction to a COVID-19 vaccine. Recent emerging evidence indicate that protecting vulnerable populations from getting COVID-19 could help prevent viral evolution that is an important factor in the emergence of variants.9

Agreements are in place to supply the US with 1.7 million units of Evusheld, each containing one 150mg vial of tixagevimab and one 150mg vial of cilgavimab. Delivery of approximately 1.2 million units is anticipated by the end of the first quarter of 2022, with the remaining deliveries being completed by the end of 2022. Evusheld also has early access use for the prophylaxis of COVID-19 and is being supplied in several other countries.

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 convalescent patients after SARS-CoV-2 virus. Discovered by Vanderbilt University Medical Center and licensed to AstraZeneca in June 2020, the human monoclonal antibodies bind to distinct sites on the SARS-CoV-2 spike protein10 and were optimised by AstraZeneca with half-life extension and reduced Fc receptor and complement C1q binding. The half-life extension more than triples the durability of its action compared to conventional antibodies;11-13 data from the Phase III PROVENT trial show protection lasting at least six months.14 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.15

The previously authorised pre-exposure prophylaxis dose for Evusheld in the US is 150mg IM each of tixagevimab and cilgavimab, with subsequent repeat dosing every six months. That dose was based on positive high-level results from the PROVENT Phase III pre-exposure prophylaxis trial and is supported by additional clinical data gathered from PROVENT, which is ongoing, laboratory data and modelling assumptions conducted against Omicron using standard methodologies.

The primary data supporting the Evusheld EUA are from the ongoing PROVENT Phase III pre-exposure prevention trial, which showed a statistically significant reduction (77% at primary analysis, 83% at median six-month analysis) in the risk of developing symptomatic COVID-19 compared to placebo, with protection from the virus continuing for at least six months. More follow-up is needed to establish the full duration of protection provided by Evusheld. Evusheld was well-tolerated in the trials.

In October 2021, AstraZeneca announced positive high-level results from the TACKLE Phase III outpatient treatment trial in which a 600mg IM dose of Evusheld was generally well-tolerated.

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 and follow the Company on Twitter @AstraZeneca.

References

  1. 1. FACT SHEET FOR HEALTHCARE PROVIDERS: EMERGENCY USE AUTHORIZATION FOR EVUSHELD™ (tixagevimab co-packaged with cilgavimab). Available at: https://www.fda.gov/media/154701/download [Last accessed: February 2022].
  2. 2. VanBlargan, LA, et al. An infectious SARS-CoV-2 B.1.1.529 Omicron virus escapes neutralization by therapeutic monoclonal antibodies. Nat Med (2022). https://doi.org/10.1038/s41591-021-01678-y.
  3. 3. Dejnirattisai W, et al. SARS-CoV-2 Omicron-B.1.1.529 leads to widespread escape from neutralizing antibody responses. Cell. 2022 Feb 3;185(3):467-484.e15.
  4. 4. National Institutes of Health. National Center for Advancing Translational Sciences Open Data Portal. SARS-CoV-2 Variants & Therapeutics. AZD7442 (AZD8895 and AZD1061; mAbs for SARS-CoV-2) Omicron Antiviral Resistance Information. Available at: https://opendata.ncats.nih.gov/variant/datasets?id=160 [Last accessed February 2022].
  5. 5. Centers for Disease Control and Prevention. COVID-19 data tracker variant proportions. Available at : https://covid.cdc.gov/covid-data-tracker/#variant-proportions [Last accessed: February 2022].
  6. 6. GISAID. COVID CoV Genomics (CG). Available from: https://covidcg.org/. [Last accessed: February 2022].
  7. 7. World Health Organization. Weekly epidemiological update on COVID-19 - 22 February 2022. Available from: https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---22-february-2022 [Last accessed: February 2022].
  8. 8. Plesner Lyngse F, et al. Transmission of SARS-CoV-2 Omicron VOC subvariants BA.1 and BA.2: Evidence from Danish Households. medRxiv 2022.01.28.22270044; doi: https://doi.org/10.1101/2022.01.28.22270044.
  9. 9. Corey L, et al. SARS-CoV-2 Variants in Patients with Immunosuppression. N Engl J Med 2021; 385:562-566. DOI: 10.1056/NEJMsb2104756.
  10. 10. Dong J, et al. Genetic and structural basis for recognition of SARS-CoV-2 spike protein by a two-antibody cocktail. bioRxiv. 2021; doi: 10.1101/2021.01.27.428529.
  11. 11. Robbie GJ, et al. A novel investigational Fc-modified humanized monoclonal antibody, motavizumab-YTE, has an extended half-life in healthy adults. Antimicrob Agents Chemother. 2013; 57 (12): 6147-53.
  12. 12. 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): e01714-16.
  13. 13. 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.
  14. 14. AstraZeneca news release. New analyses of two AZD7442 COVID-19 trials in high-risk populations confirm robust efficacy and long-term prevention. Available at: https://www.astrazeneca.com/media-centre/press-releases/2021/new-analyses-of-two-azd7442-covid-19-phase-iii-trials-in-high-risk-populations-confirm-robust-efficacy-and-long-term-prevention.html. [Last accessed: February 2022].
  15. 15. van Erp EA, et al. Fc-mediated antibody effector functions during respiratory syncytial virus infection and disease. Front Immunol. 2019; 10: 548.

Source: AstraZeneca

Posted: February 2022

Evusheld (tixagevimab co-packaged with cilgavimab) FDA Approval History

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