Tixagevimab/cilgavimab

Tixagevimab/cilgavimab, sold under the brand name Evusheld, is a combination of two human monoclonal antibodies, tixagevimab (AZD8895) and cilgavimab (AZD1061) targeted against the surface spike protein of SARS-CoV-2[18][19] used to prevent COVID-19.[20] It is being developed by British-Swedish multinational pharmaceutical and biotechnology company AstraZeneca.[21][22] It is co-packaged and given as two separate consecutive intramuscular injections (one injection per monoclonal antibody, given in immediate succession).[13]

Tixagevimab/cilgavimab
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
AHFS/Drugs.comMonograph
MedlinePlusa621058
License data
Pregnancy
category
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

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 (tixagevimab) and AZD1061 (cilgavimab), respectively (and the combination was called AZD7442).[23]

To evaluate the potential of the antibodies 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.[24][25] 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,[22] and the Omicron variant.[26]

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.[24]

Society and culture

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.[27] It was approved for medical use in the European Union in March 2022.[16]

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).[28]

In November 2021, Bahrain authorized it for emergency use.[29]

In December 2021, the U.S. Food and Drug Administration (FDA) granted emergency use authorization (EUA) 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.[30] and in certain people aged 12 years of age and older weighing at least 40 kilograms (88 lb).[13] The product is only authorized for those individuals who are not infected with the SARS-CoV-2 virus and who have not recently been exposed to an individual infected with SARS-CoV-2.[13]

Although Evusheld is FDA-approved for emergency use in the U.S, it is estimated that around 80% of the available doses sit unused in warehouses and on pharmacy and hospital shelves due to confusion among patients and health care providers.[31][32][33]

In March 2022, the European Medicines Agency's (EMA) committee CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Evusheld, intended for the pre-exposure prophylaxis of COVID-19 in adults and adolescents aged 12 years and older weighing at least 40 kilograms (88 lb).[34] The applicant for this medicinal product is AstraZeneca AB.[34] It has since been granted approval for use in the UK[35][36] and in the European Union.[16][37]

In January 2023, the FDA revised the EUA for Evusheld to limit its use to when the combined frequency of non-susceptible SARS-CoV-2 variants nationally is less than or equal to 90%.[38] Based on this revision, Evusheld is not authorized for use in the US.[38]

References
  1. "Evusheld APMDS". Therapeutic Goods Administration (TGA). 7 March 2022. Archived from the original on 24 March 2022. Retrieved 23 March 2022.
  2. "Updates to the Prescribing Medicines in Pregnancy database". Therapeutic Goods Administration (TGA). 21 December 2022. Archived from the original on 3 April 2022. Retrieved 2 January 2023.
  3. "Evusheld APMDS". Therapeutic Goods Administration (TGA). 21 December 2022. Archived from the original on 5 January 2023. Retrieved 4 January 2023.
  4. "Evusheld". Therapeutic Goods Administration (TGA). Archived from the original on 24 March 2022. Retrieved 23 March 2022.
  5. "AusPAR: Tixagevimab and cilgavimab". Therapeutic Goods Administration (TGA). 11 March 2022. Archived from the original on 24 March 2022. Retrieved 23 March 2022.
  6. Archived copy Archived 5 January 2023 at the Wayback Machine
  7. "Evusheld Product information". Health Canada. 25 April 2012. Archived from the original on 29 May 2022. Retrieved 29 May 2022.
  8. "Evusheld". Health Canada. 14 April 2022. Archived from the original on 14 April 2022. Retrieved 31 May 2022.
  9. "Summary Basis of Decision – Evusheld". Health Canada. 23 October 2014. Archived from the original on 6 August 2022. Retrieved 6 August 2022.
  10. "Regulatory approval of Evusheld (tixagevimab/cilgavimab)". Medicines & Healthcare products Regulatory Agency. 17 March 2022. Archived from the original on 10 June 2022. Retrieved 10 June 2022.
  11. "Summary of Product Characteristics for Evusheld". Medicines & Healthcare products Regulatory Agency. 17 March 2022. Archived from the original on 10 June 2022. Retrieved 10 June 2022.
  12. "Evusheld- azd7442 kit". DailyMed. AstraZeneca. 20 December 2021. Archived from the original on 5 January 2022. Retrieved 20 January 2022.
  13. "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. Archived from the original on 28 April 2022. Retrieved 9 December 2021. Public Domain This article incorporates text from this source, which is in the public domain.
  14. 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.
  15. "FDA authorizes revisions to Evusheld dosing". U.S. Food and Drug Administration (FDA). 24 February 2022. Archived from the original on 27 February 2022. Retrieved 27 February 2022.
  16. "Evusheld EPAR". European Medicines Agency (EMA). 22 March 2022. Archived from the original on 16 April 2022. Retrieved 24 April 2022.
  17. "Evusheld". Union Register of medicinal products. 25 March 2022. Archived from the original on 28 March 2022. Retrieved 24 April 2022.
  18. "Cilgavimab". IUPHAR/BPS Guide to Pharmacology. IUPHAR. 27 December 2021. Archived from the original on 27 December 2021. Retrieved 27 December 2021.
  19. "Tixagevimab". IUPHAR/BPS Guide to Pharmacology. IUPHAR. 27 December 2021. Archived from the original on 27 December 2021. Retrieved 27 December 2021.
  20. 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.
  21. 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.
  22. 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.
  23. 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. 6 (10): 1233–1244. doi:10.1038/s41564-021-00972-2. LCCN 2016247755. OCLC 959654134. PMC 8543371. PMID 34548634.
  24. Haridy R (23 August 2021). ""Game-changing" antibody cocktail prevents COVID-19 in the chronically ill". New Atlas. Archived from the original on 10 October 2021. Retrieved 23 August 2021.
  25. "AZD7442 PROVENT Phase III prophylaxis trial met primary endpoint in preventing COVID-19". AstraZeneca (Press release). 20 August 2021. Archived from the original on 19 November 2021. Retrieved 15 October 2021.
  26. "AstraZeneca COVID drug neutralises Omicron sub-variants in lab study". Reuters. 21 March 2022. Archived from the original on 22 April 2022. Retrieved 5 April 2022.
  27. "EMA starts rolling review of Evusheld (tixagevimab and cilgavimab)". European Medicines Agency (EMA). 14 October 2021. Archived from the original on 8 November 2021. Retrieved 15 October 2021.
  28. "AZD7442 request for Emergency Use Authorization for COVID-19 prophylaxis filed in US". AstraZeneca (Press release). 5 October 2021. Archived from the original on 15 October 2021. Retrieved 15 October 2021.
  29. 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.
  30. 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.
  31. Cohen E, Herman D (24 March 2022). "Vulnerable Americans are desperate to find this Covid-19 drug. Thousands of boxes are sitting around unused". CNN. Archived from the original on 15 April 2022. Retrieved 5 April 2022.
  32. Morris A, Stolberg SG (6 March 2022). "High Demand for Drug to Prevent Covid in the Vulnerable, Yet Doses Go Unused". The New York Times. ISSN 0362-4331. Archived from the original on 24 April 2022. Retrieved 5 April 2022.
  33. "It was already hard to find Evusheld COVID prevention therapy. Now it's harder". The Seattle Times. 21 March 2022. Archived from the original on 18 April 2022. Retrieved 5 April 2022.
  34. "Evusheld: Pending EC decision". European Medicines Agency (EMA). 25 March 2022. Archived from the original on 25 March 2022. Retrieved 25 March 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  35. "AstraZeneca's Evusheld Covid-prevention drug gets UK approval". The Guardian. 17 March 2022. Archived from the original on 25 April 2022. Retrieved 5 April 2022.
  36. Fourcade M. "Astra Covid Antibody Gets U.K. Approval for People With Poor Immunity". Bloomberg. Archived from the original on 6 April 2022. Retrieved 5 April 2022.
  37. "New drug that prevents you from catching COVID-19 given green light in Europe". Fortune. Archived from the original on 25 April 2022. Retrieved 5 April 2022.
  38. "Latest FDA Updates for Evusheld". U.S. Food and Drug Administration. 26 January 2023. Archived from the original on 14 March 2023. Retrieved 26 January 2023. Public Domain This article incorporates text from this source, which is in the public domain.
Wikimedia Commons has media related to AZD7442.
  • "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
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