Casirivimab/imdevimab

Casirivimab/imdevimab
REGN10933 (blue) and REGN10987 (orange) bound to SARS-CoV-2 spike protein (pink). From PDB: 6VSB, 6XDG​.
Combination of
CasirivimabMonoclonal antibody against SARS-CoV-2
ImdevimabMonoclonal antibody against SARS-CoV-2
Names
Trade namesREGEN-COV, Ronapreve
Other namesREGN-COV2
Clinical data
Main usesTreat and prevent COVID-19[1]
Side effectsInfusion reaction, redness at the site of injection, anaphylaxis, fever, breathing problems[1]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
    Routes of
    use    		Intravenous, subcutaneous injection
    External links
    AHFS/Drugs.comMonograph
    Legal
    License data
    Legal status

    Casirivimab/imdevimab, sold under the brand name REGEN-COV among others, is a medication used to treat and prevent COVID-19.[1] As treatment it is used in mild to moderate disease in those at high risk.[1] It works much less well in those with the Omicron variant.[7][8] It is given by injection under the skin or into a vein.[1]

    Common side effects include infusion reaction and redness at the site of injection.[1] Other side effects may include anaphylaxis, fever, and breathing problems.[1] While it may be used in pregnancy, safety is unclear.[1] It is two monoclonal antibodies, casirivimab (REGN10933) and imdevimab (REGN10987) which bind to the virus.[5][9]

    The combination is available under an emergency use authorization in the United States as of 2021.[1] It is approved for medical use in Australia, the UK, and Japan.[10][11][2] In the United States the government has purchased doses at 2,100 USD each, which they provide free.[12] In Germany it was purchased for about €2,000 per dose.[13]

    Medical uses

    It may be used for mild to moderate disease among those who are at high risk, but is not recommended for those who newly require oxygen or hospitalization.[5] It is not recommended as an alternative to vaccination.[5]

    Evidence supports a probable decreased risk of hospitalization but not a change in risk of death or length of hospitalization as of November 2021.[14][15] It appears to works less well in those with the Omicron variant.[7]

    Dosage

    For treatment it is given as a single dose of dose of 600 mg casirivimab and 600 mg of imdevimab, either intravenous or by sub Q injection.[1] A full or a half-dose may be used for prevention.[1] In Europe a dose of 1,200 / 1,200 mg is recommended.[16]

    Mechanism of action

    The combination of two antibodies is intended to prevent mutational escape.[17]

    History

    It is manufactured at the Regeneron's manufacturing facility in Rensselaer, New York.[18] In September 2020, to free up manufacturing capacity for REGEN-COV, Regeneron began to shift production of its existing products from Rensselaer to the Irish city of Limerick.[19]

    Regeneron has a deal in place with Roche (Genentech)[20] to manufacture and market the medication outside the United States.[21][22]

    Society and culture

    The United States paused delivery of this medication on December 23, 2021 due to the lack of benefit for Omicron.[23]

    Cost

    On 12 January 2021, the United States government agreed to purchase 1.25 million doses of the drug for $2.625 billion, at $2,100 per dose.[24][25] On 14 September, another 1.4 million doses were purchased for the same price, totaling $2.94 billion.[26]

    On 24 January, the German government purchased 200,000 doses for €400 million at €2,000 per dose.[13]

    On 25 May, Roche India and Cipla announced that the medicine would be available in India for Rs 59,750 (800 USD) per dose.[27]

    On 24 September, the World Health Organization urged producers and governments to address the drug's high cost and called for technology sharing to enable the manufacture of biosimilar versions. The WHO also said that Unitaid is negotiating with Roche for lower prices and equitable distribution, especially in low- and middle income countries.[28]

    Notable uses

    On 2 October 2020, Regeneron Pharmaceuticals announced that then-US President Donald Trump had received "a single 8 gram dose of REGN-COV2" after testing positive for SARS-CoV-2.[29][30] The drug was provided by the company in response to a "compassionate use" (temporary authorization for use) request from the president's physicians.[29]

    In August 2021, Texas Governor Greg Abbott received REGEN-COV after testing positive for COVID-19.[31]

    Research

    COVID-19

    In a clinical trial of people with COVID-19, casirivimab and imdevimab, administered together, were shown to reduce COVID-19-related hospitalization or emergency room visits in people at high risk for disease progression within 28 days after treatment when compared to placebo.[32] The safety and effectiveness of this investigational therapy for use in the treatment of COVID-19 continues to be evaluated.[32]

    The data supporting the emergency use authorization (EUA) for casirivimab and imdevimab are based on a randomized, double-blind, placebo-controlled clinical trial in 799 non-hospitalized adults with mild to moderate COVID-19 symptoms.[32] Of these participants, 266 received a single intravenous infusion of 2,400 milligrams casirivimab and imdevimab (1,200 mg of each), 267 received 8,000 mg casirivimab and imdevimab (4,000 mg of each), and 266 received a placebo, within three days of obtaining a positive SARS-CoV-2 viral test.[32]

    The prespecified primary endpoint for the trial was time-weighted average change in viral load from baseline.[32] Viral load reduction in participants treated with casirivimab and imdevimab was larger than in participants treated with placebo at day seven.[32] However, the most important evidence that casirivimab and imdevimab administered together may be effective came from the predefined secondary endpoint of medically attended visits related to COVID-19, particularly hospitalizations and emergency room visits within 28 days after treatment.[32] For participants at high risk for disease progression, hospitalizations and emergency room visits occurred in 3% of casirivimab and imdevimab-treated participants on average compared to 9% in placebo-treated participants.[32] The effects on viral load, reduction in hospitalizations and ER visits were similar in participants receiving either of the two casirivimab and imdevimab doses.[32]

    Since September 2020 REGEN-COV is being evaluated as part of the RECOVERY Trial,[33] and in June 2021 the first results of the research were announced with evidence proving the effectiveness of the treatment.

    On 21 November 2020, the U.S. Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for casirivimab and imdevimab to be administered together for the treatment of mild to moderate COVID-19 in people twelve years of age or older weighing at least 40 kilograms (88 lb) with positive results of direct SARS-CoV-2 viral testing and who are at high risk for progressing to severe COVID-19.[32][21][34][35] This includes those who are 65 years of age or older or who have certain chronic medical conditions.[32] Casirivimab and imdevimab must be administered together by intravenous (IV) infusion.[32]

    Casirivimab and imdevimab are not authorized for people who are hospitalized due to COVID-19 or require oxygen therapy due to COVID-19.[32] A benefit of casirivimab and imdevimab treatment has not been shown in people hospitalized due to COVID-19.[32] Monoclonal antibodies, such as casirivimab and imdevimab, may be associated with worse clinical outcomes when administered to hospitalized people with COVID-19 requiring high flow oxygen or mechanical ventilation.[32] In June 2021, the EUA was revised to authorize "the use of the unapproved product, REGEN-COV (casirivimab and imdevimab) co-formulated product and REGEN-COV (casirivimab and imdevimab) supplied as individual vials to be administered together, for the treatment of mild to moderate COVID-19 in people aged twelve years of age and older weighing at least 40 kilograms (88 lb) with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death."[34][5]

    The EUA was issued to Regeneron Pharmaceuticals Inc.[32][21][35][36]

    On 1 February 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) started a rolling review of data on the REGN‑COV2 antibody combination (casirivimab/imdevimab), which is being co-developed by Regeneron Pharmaceuticals, Inc. and F. Hoffman-La Roche, Ltd (Roche) for the treatment and prevention of COVID‑19.[37][38] In February 2021, the CHMP concluded that the combination, also known as REGN-COV2, can be used for the treatment of confirmed COVID-19 in people who do not require supplemental oxygen and who are at high risk of progressing to severe COVID-19.[39]

    The Central Drugs Standards Control Organisation (CDSCO) in India, on 5 May 2021, granted an Emergency Use Authorization to Roche (Genentech)[20] and Regeneron[40] for use of the casirivimab/imdevimab cocktail in the country. The announcement came in light of the second wave of the COVID-19 pandemic in India. Roche India maintains partnership with Cipla, thereby permitting the latter to market the drug in the country.[41]

    In July 2021, the U.S. FDA revised the emergency use authorization (EUA) for REGEN-COV (casirivimab and imdevimab, administered together) authorizing REGEN-COV for emergency use as post-exposure prophylaxis (prevention) for COVID-19 in people aged twelve years of age and older weighing at least 40 kilograms (88 lb) who are at high risk for progression to severe COVID-19, including hospitalization or death.[42] REGEN-COV remains authorized for the treatment of mild-to-moderate COVID-19 in people aged twelve years of age and older weighing at least 40 kilograms (88 lb) with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death.[42]

    On 12 April 2021, Roche (Genentech)[20] and Regeneron announced that the Phase III clinical trial REGN-COV 2069 met both primary and secondary endpoints, reducing risk of infection by 81% for the non-infected participants, and reducing time-to-resolution of symptoms for symptomatic participants to one week vs. three weeks in the placebo group.[43]

    On 16 June 2021, preliminary form the Recovery trial showed reduced mortality from 30% to 24% in patients that had produced no antibodies themselves which were 33% of the total of participants.[44][45][46][47]

    References

    1. 1 2 3 4 5 6 7 8 9 10 11 "Casirivimab and Imdevimab Monograph for Professionals". Drugs.com. Archived from the original on 21 October 2021. Retrieved 6 November 2021.
    2. 1 2 3 "Ronapreve". Therapeutic Goods Administration (TGA). 18 October 2021. Archived from the original on 23 October 2021. Retrieved 22 October 2021.
    3. ↑ "COVID-19 treatment: Roche Products Pty Ltd, casirivimab + imdevimab (Ronapreve)". Therapeutic Goods Administration (TGA). 15 October 2021. Archived from the original on 24 October 2021. Retrieved 22 October 2021.
    4. ↑ "Summary of Product Characteristics for Ronapreve". Medicines and Healthcare products Regulatory Agency (MHRA). 20 August 2021. Archived from the original on 30 August 2021. Retrieved 29 August 2021.
    5. 1 2 3 4 5 "Casirivimab injection, solution, concentrate Imdevimab injection, solution, concentrate REGEN-COV – casirivimab and imdevimab kit". DailyMed. Archived from the original on 4 January 2021. Retrieved 18 March 2021.
    6. ↑ "Japan becomes first country to approve Ronapreve (casirivimab and imdevimab) for the treatment of mild to moderate COVID-19". Roche (Press release). 20 July 2021. Archived from the original on 24 July 2021. Retrieved 29 August 2021.
    7. 1 2 Kozlov, Max (21 December 2021). "Omicron overpowers key COVID antibody treatments in early tests". Nature. doi:10.1038/d41586-021-03829-0. Archived from the original on 22 December 2021. Retrieved 23 December 2021.
    8. ↑ "Statement on Therapies for High-Risk, Nonhospitalized Patients". COVID-19 Treatment Guidelines. Archived from the original on 7 January 2022. Retrieved 6 January 2022.
    9. ↑ "Casirivimab + imdevimab". SPS - Specialist Pharmacy Service. 26 December 2020. Archived from the original on 6 November 2021. Retrieved 6 November 2021.
    10. ↑ "Regulatory approval of Ronapreve". Medicines and Healthcare products Regulatory Agency (MHRA). 20 August 2021. Archived from the original on 30 August 2021. Retrieved 29 August 2021.
    11. ↑ Tsukimori, Osamu (5 November 2021). "Japan OKs use of 'antibody cocktail' to prevent COVID-19". The Japan Times. Archived from the original on 6 November 2021. Retrieved 6 November 2021.
    12. ↑ Jarvis, Jacob (12 October 2021). "Fact Check: Regeneron monoclonal antibody costs government $2,100 per dose". Newsweek. Archived from the original on 4 November 2021. Retrieved 6 November 2021.
    13. 1 2 "Coronavirus: Germany to use new antibody-based drug". DW. 24 January 2021. Archived from the original on 8 October 2021. Retrieved 30 September 2021.
    14. ↑ "Treatments". www.bccdc.ca. Archived from the original on 9 October 2021. Retrieved 6 November 2021.
    15. ↑ Siemieniuk, RA; Bartoszko, JJ; Díaz Martinez, JP; Kum, E; Qasim, A; Zeraatkar, D; Izcovich, A; Mangala, S; Ge, L; Han, MA; Agoritsas, T; Arnold, D; Ávila, C; Chu, DK; Couban, R; Cusano, E; Darzi, AJ; Devji, T; Foroutan, F; Ghadimi, M; Khamis, A; Lamontagne, F; Loeb, M; Miroshnychenko, A; Motaghi, S; Murthy, S; Mustafa, RA; Rada, G; Rochwerg, B; Switzer, C; Vandvik, PO; Vernooij, RW; Wang, Y; Yao, L; Guyatt, GH; Brignardello-Petersen, R (23 September 2021). "Antibody and cellular therapies for treatment of covid-19: a living systematic review and network meta-analysis". BMJ (Clinical research ed.). 374: n2231. doi:10.1136/bmj.n2231. PMID 34556486.
    16. ↑ "CONDITIONS OF USE, CONDITIONS FOR DISTRIBUTION, PATIENTS TARGETED AND CONDITIONS FOR SAFETY MONITORING ADRESSED TO MEMBER STATES" (PDF). Archived (PDF) from the original on 2 November 2021. Retrieved 6 November 2021.
    17. ↑ Baum A, Fulton BO, Wloga E, Copin R, Pascal KE, Russo V, et al. (August 2020). "Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies". Science. 369 (6506): 1014–1018. Bibcode:2020Sci...369.1014B. doi:10.1126/science.abd0831. PMC 7299283. PMID 32540904.
    18. ↑ Williams, Stephen (3 October 2020). "Experimental drug given to President made locally". The Daily Gazette. Archived from the original on 1 November 2020. Retrieved 23 October 2021.
    19. ↑ Stanton, Dan (11 September 2020). "Manufacturing shift to Ireland frees up US capacity for Regeneron's COVID antibodies". BioProcess International. Archived from the original on 9 November 2020. Retrieved 23 October 2021.
    20. 1 2 3 "Genentech and Regeneron Collaborate to Significantly Increase Global Supply of REGN-COV2 Investigational Antibody Combination for COVID-19" (Press release). Genentech. 19 August 2020. Archived from the original on 2 June 2021. Retrieved 8 June 2021 – via Business Wire.
    21. 1 2 3 "Regeneron Reports Positive Interim Data with REGEN-COV Antibody Cocktail used as Passive Vaccine to Prevent COVID-19" (Press release). Regeneron Pharmaceuticals. 26 January 2021. Archived from the original on 19 March 2021. Retrieved 19 March 2021 – via PR Newswire.
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    27. ↑ "Roche's Antibody Cocktail launched in India at Rs 59,750/dose". The Indian Express. 25 May 2021. Archived from the original on 30 September 2021. Retrieved 30 September 2021.
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    29. 1 2 Thomas K (2 October 2020). "President Trump Received Experimental Antibody Treatment". The New York Times. ISSN 0362-4331. Archived from the original on 4 October 2020. Retrieved 2 October 2020.
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    31. ↑ Schneider A (17 August 2021). "Texas Gov. Greg Abbott Tests Positive For The Coronavirus". NPR. Archived from the original on 19 August 2021. Retrieved 17 August 2021.
    32. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 "Coronavirus (COVID-19) Update: FDA Authorizes Monoclonal Antibodies for Treatment of COVID-19". U.S. Food and Drug Administration (FDA) (Press release). 21 November 2020. Archived from the original on 25 January 2021. Retrieved 21 November 2020. Public Domain This article incorporates text from this source, which is in the public domain.
    33. ↑ "RECOVERY COVID-19 phase 3 trial to evaluate Regeneron's REGN-COV2 investigational antibody cocktail in the UK". Recovery Trial. 14 September 2020. Archived from the original on 21 January 2021. Retrieved 23 October 2021.
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    41. ↑ "Roche receives Emergency Use Authorisation in India for its investigational Antibody Cocktail (Casirivimab and Imdevimab) used in the treatment of Covid-19". Cipla. Archived from the original on 14 June 2021. Retrieved 6 May 2021.
    42. 1 2 "FDA authorizes REGEN-COV monoclonal antibody therapy for post-exposure prophylaxis (prevention) for COVID-19". U.S. Food and Drug Administration (FDA). 30 July 2021. Archived from the original on 30 July 2021. Retrieved 30 July 2021. Public Domain This article incorporates text from this source, which is in the public domain.
    43. ↑ "Phase III prevention trial showed subcutaneous administration of investigational antibody cocktail casirivimab and imdevimab reduced risk of symptomatic COVID-19 infections by 81%". streetinsider.com. 12 April 2021. Archived from the original on 12 April 2021. Retrieved 12 April 2021.
    44. ↑ Kupferschmidt K (16 June 2021). "Monoclonal antibodies cut risk of dying from COVID-19 – but only in some patients". Science. doi:10.1126/science.abk0053 (inactive 30 August 2021). A paper with the results will be made available on the medRxiv preprint server later today, the researchers say.{{cite journal}}: CS1 maint: DOI inactive as of August 2021 (link)
    45. ↑ Group, RECOVERY Collaborative; Horby, Peter W.; Mafham, Marion; Peto, Leon; Campbell, Mark; Pessoa-Amorim, Guilherme; Spata, Enti; Staplin, Natalie; Emberson, Jonathan R.; Prudon, Benjamin; Hine, Paul (16 June 2021). "Casirivimab and imdevimab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial": 2021.06.15.21258542. doi:10.1101/2021.06.15.21258542v1. Archived from the original on 29 September 2021. Retrieved 23 October 2021. {{cite journal}}: Cite journal requires |journal= (help)
    46. ↑ "RECOVERY trial finds Regeneron's monoclonal antibody combination reduces deaths for hospitalised COVID-19 patients who have not mounted their own immune response — RECOVERY Trial". www.recoverytrial.net. Archived from the original on 4 October 2021. Retrieved 4 October 2021.
    47. ↑ "Another life-saving Covid treatment found". BBC News. 16 June 2021. Archived from the original on 4 October 2021. Retrieved 4 October 2021.
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