Tixagevimab/cilgavimab

Tixagevimab/cilgavimab
Tixagevimab-cilgavimab binding SARS-CoV-2 spike protein 7L7E.png
Tixagevimab (teal, right) and cilgavimab (purple, left) binding the spike protein RBD. From PDB: 7L7E​.
Combination of
TixagevimabMonoclonal antibody
CilgavimabMonoclonal antibody
Clinical data
Trade namesEvusheld
Other namesAZD7442
License data
Routes of
administration
Intramuscular
ATC code
Legal status
Legal status
Identifiers
KEGG
Tixagevimab
Clinical data
Drug classAntiviral
ATC code
  • None
Identifiers
CAS Number
DrugBank
UNII
KEGG
Chemical and physical data
FormulaC6488H10034N1746O2038S50
Molar mass146706.82 g·mol−1
Cilgavimab
Clinical data
Drug classAntiviral
ATC code
  • None
Identifiers
CAS Number
DrugBank
UNII
KEGG
Chemical and physical data
FormulaC6626H10218N1750O2078S44
Molar mass149053.44 g·mol−1

Tixagevimab/cilgavimab (Evusheld) is a combination of two human monoclonal antibodies, tixagevimab (AZD8895) and cilgavimab (AZD1061) targeted against the surface spike protein of SARS-CoV-2[5][6] used to prevent COVID-19.[7] It is being developed by British-Swedish multinational pharmaceutical and biotechnology company AstraZeneca.[8][9] It is co-packaged and given as two separate consecutive intramuscular injections (one injection per monoclonal antibody, given in immediate succession).[2]

Development

In 2020, researchers at Vanderbilt University Medical Center discovered particularly potent monoclonal antibodies, isolated from COVID-19 patients infected with a SARS-CoV-2 circulating at that time. Initially designated COV2-2196 and COV2-2130, antibody engineering was used to transfer their SARS-CoV-2 binding specificity to IgG scaffolds that would last longer in the body, and these engineered antibodies were named AZD8895 and AZD1061, respectively (and the combination was called AZD7442).[10]

To evaluate the antibodies' potential as monoclonal antibody based prophylaxis (prevention), the 'Provent' clinical trial enrolled 5,000 high risk but not yet infected individuals and monitored them for 15 months.[11][12] The trial reported that those receiving the cocktail showed a 77% reduction in symptomatic COVID-19 and that there were no severe cases or deaths. AstraZeneca also found that the antibody cocktail "neutralizes recent emergent SARS-CoV-2 viral variants, including the Delta variant".[9]

In contrast to pre-exposure prophylaxis, the Storm Chaser study of already-exposed people (post-exposure prophylaxis) did not meet its primary endpoint, which was prevention of symptomatic COVID-19 in people already exposed. AZD7442 was administered to 1,000 volunteers who had recently been exposed to COVID.[11]

Regulatory review

In October 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) started a rolling review of tixagevimab/cilgavimab, which is being developed by AstraZeneca AB, for the prevention of COVID-19 in adults.[13]

Also in October 2021, AstraZeneca requested Emergency Use Authorization for tixagevimab/cilgavimab to prevent COVID-19 from the U.S. Food and Drug Administration (FDA).[14][15]

Emergency use authorization

On 14 November 2021, Bahrain granted emergency use authorization.[16]

On 8 December 2021, the U.S. Food and Drug Administration (FDA) granted emergency use authorization of this combination to prevent COVID-19 (before exposure) in people with weakened immunity or who cannot be fully vaccinated due to a history of severe reaction to coronavirus vaccines.[17] The FDA issued an emergency use authorization (EUA) for AstraZeneca's Evusheld (tixagevimab co-packaged with cilgavimab and administered together) for the pre-exposure prophylaxis (prevention) of COVID-19 in certain people aged 12 years of age and older weighing at least 40 kilograms (88 lb).[2] The product is only authorized for those individuals who are not currently infected with the SARS-CoV-2 virus and who have not recently been exposed to an individual infected with SARS-CoV-2.[2]

Distribution

In the first weeks after U.S. approval, supplies were rationed by the federal government to state governments based on population alone. This led to adequate supply in some states, like Alaska, but undersupply in states with active transplant medical facilities, like Colorado, Massachusetts, and Washington. Some hospitals ranked patients by medical need, then conducted a lottery to ration doses to the highest-ranked patients.[18]

References

  1. ^ "EVUSHELD- azd7442 kit". DailyMed. NIH NLM. National Institutes of Health. 20 December 2021. Archived from the original on 5 January 2022. Retrieved 20 January 2022.
  2. ^ a b c d "Coronavirus (COVID-19) Update: FDA Authorizes New Long-Acting Monoclonal Antibodies for Pre-exposure Prevention of COVID-19 in Certain Individuals". U.S. Food and Drug Administration (FDA) (Press release). 8 December 2021. Retrieved 9 December 2021. Public Domain This article incorporates text from this source, which is in the public domain.
  3. ^ O'Shaughnessy A (20 December 2021). "Re: Emergency Use Authorization 104" (PDF). Food and Drug Administration. Letter to AstraZeneca Pharmaceuticals LP | Attention: Stacey Cromer Berman, PhD. Archived from the original on 29 December 2021. Retrieved 18 January 2022.
  4. ^ "FDA authorizes revisions to Evusheld dosing". U.S. Food and Drug Administration (FDA). 24 February 2022. Retrieved 27 February 2022.
  5. ^ "Cilgavimab". IUPHAR/BPS Guide to PHARMACOLOGY. IUPHAR. 27 December 2021. Retrieved 27 December 2021.
  6. ^ "Tixagevimab". IUPHAR/BPS Guide to PHARMACOLOGY. IUPHAR. 27 December 2021. Retrieved 27 December 2021.
  7. ^ Abramowicz M, Zuccotti G, Pflomm JM, eds. (January 2022). "Tixagevimab and Cilgavimab (Evusheld) for Pre-Exposure Prophylaxis of COVID-19". JAMA. 327 (4): 384–385. doi:10.1001/jama.2021.24931. PMID 35076671.
  8. ^ Ray S (21 August 2021). "AstraZeneca's Covid-19 Antibody Therapy Effective In Preventing Symptoms Among High-Risk Groups, Trial Finds". Forbes. ISSN 0015-6914. Archived from the original on 21 August 2021. Retrieved 18 January 2022.
  9. ^ a b Goriainoff AO (20 August 2021). "AstraZeneca Says AZD7442 Antibody Phase 3 Trial Met Primary Endpoint in Preventing Covid-19". MarketWatch. Archived from the original on 21 August 2021. Retrieved 18 January 2022.
  10. ^ Dong J, Zost SJ, Greaney AJ, Starr TN, Dingens AS, Chen EC, et al. (October 2021). "Genetic and structural basis for SARS-CoV-2 variant neutralization by a two-antibody cocktail". Nature Microbiology (published 21 September 2021). 6 (10): 1233–1244. doi:10.1038/s41564-021-00972-2. LCCN 2016247755. OCLC 959654134. PMC 8543371. PMID 34548634.
  11. ^ a b Haridy R (23 August 2021). ""Game-changing" antibody cocktail prevents COVID-19 in the chronically ill". New Atlas. Retrieved 23 August 2021.
  12. ^ "AZD7442 PROVENT Phase III prophylaxis trial met primary endpoint in preventing COVID-19". AstraZeneca (Press release). 20 August 2021. Retrieved 15 October 2021.
  13. ^ "EMA starts rolling review of Evusheld (tixagevimab and cilgavimab)". European Medicines Agency. 14 October 2021. Retrieved 15 October 2021.
  14. ^ "AZD7442 request for Emergency Use Authorization for COVID-19 prophylaxis filed in US". AstraZeneca US (Press release). 5 October 2021. Retrieved 15 October 2021.
  15. ^ "AZD7442 request for Emergency Use Authorization for COVID-19 prophylaxis filed in US". AstraZeneca (Press release). 5 October 2021. Retrieved 15 October 2021.
  16. ^ Abd-Alaziz M, Elhamy A (14 November 2021). Macfie N (ed.). "Bahrain authorizes AstraZeneca's anti-COVID drug for emergency use". Reuters. Archived from the original on 23 November 2021. Retrieved 18 January 2022.
  17. ^ Mishra M, Satija B (8 December 2021). Dasgupta S (ed.). "U.S. FDA authorizes use of AstraZeneca COVID-19 antibody cocktail". Reuters. Archived from the original on 13 January 2022. Retrieved 18 January 2022.
  18. ^ Huang P (25 January 2022). "Hospitals use a lottery to allocate scarce COVID drugs for the immunocompromised". NPR. Archived from the original on 26 January 2022. Retrieved 26 January 2022. But the drug is in short supply. The federal government controls distribution. It has shipped around 300,000 doses to health care providers and has ordered 1.2 million doses to date. Around 7 million people in the U.S. could benefit from the drug.

External links

  • "Tixagevimab". Drug Information Portal. U.S. National Library of Medicine.
  • "Cilgavimab". Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT04625972 for "Phase III Double-blind, Placebo-controlled Study of AZD7442 for Post-exposure Prophylaxis of COVID-19 in Adults (STORM CHASER)" at ClinicalTrials.gov
  • Clinical trial number NCT04625725 for "Phase III Double-blind, Placebo-controlled Study of AZD7442 for Pre-exposure Prophylaxis of COVID-19 in Adult. (PROVENT)" at ClinicalTrials.gov

Media files used on this page

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The rod of Asclepius as depicted in the WHO logo.
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SARS-CoV-2 logo in Wikimedia colors
Tixagevimab-cilgavimab binding SARS-CoV-2 spike protein 7L7E.png
Space-filling model of the Fab fragments of the monoclonal antibodies tixagevimab (AZD8895, teal) and cilgavimab (AZD1061, purple), the components of the Evusheld™ antibody cocktail manufactured by AstraZeneca, as bound to the receptor-binding domain (orange) of a SARS-CoV-2 spike protein.
Style made to resemble the Protein Data Bank's "Molecule of the Month" series, illustrated by Dr. David S. Goodsell of the Scripps Research Institute. Created using DS Studio Visualizer, QuteMol (http://qutemol.sourceforge.net), and GIMP. Optimized with OptiPNG.