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Casirivimab, a human immunoglobulin G-1 (IgG1) monoclonal antibody (mAb), is a covalent heterotetramer consisting of 2 heavy chains and 2 light chains produced by recombinant DNA technology in Chinese hamster ovary (CHO) cell suspension culture and has an approximate molecular weight of 145.23 kDa.
Casirivimab injection is a sterile, preservative-free, clear to slightly opalescent and colorless to pale yellow solution in a single-dose vial for intravenous infusion after dilution available as a 300 mg/2.5 mL (120 mg/mL) or 1,332 mg/11.1 mL (120 mg/mL) solution and must be administered with imdevimab. The vial stoppers are not made with natural rubber latex.
Imdevimab, a human IgG1 mAb, is a covalent heterotetramer consisting of 2 heavy chains and 2 light chains produced by recombinant DNA technology in Chinese hamster ovary (CHO) cell suspension culture and has an approximate molecular weight of 144.14 kDa.
Imdevimab injection is a sterile, preservative-free, clear to slightly opalescent and colorless to pale yellow solution in a single-dose vial for intravenous infusion after dilution available as a 300 mg/2.5 mL (120 mg/mL) or 1,332 mg/11.1 mL (120 mg/mL) solution and must be administered with casirivimab. The vial stoppers are not made with natural rubber latex.
REGEN-COV (casirivimab and imdevimab solution) injection is a sterile, preservative-free, clear to slightly opalescent, and colorless to pale yellow solution, in a single-dose vial for intravenous infusion after dilution. The vial stoppers are not made with natural rubber latex.
REGEN-COV (casirivimab and imdevimab) co-formulated product and REGEN-COV (casirivimab and imdevimab) supplied as individual vials to be administered together, is authorized for use under an EUA for the treatment of mild to moderate COVID-19 in adults and pediatric patients (12 years of age and older weighing at least 40 kg) 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.
The optimal dosing regimen for treatment of COVID-19 has not yet been established.
The recommended dosing regimen may be updated as data from clinical trials become available.
This section provides essential information on 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 adults and pediatric patients (12 years of age and older weighing at least 40 kg) 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 [see Limitations of Authorized Use].
The following medical conditions or other factors may place adults and pediatric patients (age 12-17 years and weighing at least 40 kg) at higher risk for progression to severe COVID-19:
Other medical conditions or factors (for example, race or ethnicity) may also place individual patients at high risk for progression to severe COVID-19 and authorization of REGEN-COV under the EUA is not limited to the medical conditions or factors listed above.
For additional information on medical conditions and factors associated with increased risk for progression to severe COVID-19, see the CDC website: https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html. Healthcare providers should consider the benefit-risk for an individual patient.
Casirivimab and imdevimab should be given together as soon as possible after a positive viral test for SARS-CoV-2 and within 10 days of symptom onset.
No dosage adjustment is recommended in pregnant or lactating women [see Use In Specific Populations].
No dosage adjustment is recommended in pediatric patients who weigh at least 40 kg and are older than 12 years of age. REGEN-COV (casirivimab and imdevimab) is not recommended for pediatric patients weighing less than 40 kg or those less than 12 years of age [see Use In Specific Populations].
No dosage adjustment is recommended in patients with renal impairment [see Use In Specific Populations].
There are TWO different formulations of REGEN-COV:
Intravenous infusion is strongly recommended. Subcutaneous injection is an alternative route of administration when intravenous infusion is not feasible and would lead to delay in treatment.
There are differences in the way the two formulations are prepared. Carefully follow the preparation procedures below.
The preferred route of administration for casirivimab and imdevimab is by intravenous infusion after dilution.
Casirivimab and imdevimab solution for intravenous infusion should be prepared by a qualified healthcare professional using aseptic technique:
If immediate administration is not possible, store the diluted casirivimab and imdevimab infusion solution in the refrigerator between 2°C to 8°C (36°F to 46°F) for no more than 36 hours or at room temperature up to 25°C (77°F) for no more than 4 hours. If refrigerated, allow the infusion solution to equilibrate to room temperature for approximately 30 minutes prior to administration.
Table 1: Recommended Dilution Instructions for 600 mg of Casirivimab and 600 mg of Imdevimab for Intravenous Infusion
| Size of Prefilled 0.9% Sodium Chloride Infusion Bag | Preparing Using Co-Formulated Casirivimab and Imdevimab Vial | Preparing Casirivimab and Imdevimab Using Individual Vialsa |
| 50 mL | Add 10 mL of co-formulated casirivimab and imdevimab (1 vial) into a prefilled 0.9% sodium chloride infusion bag and administer as instructed below | Add:
|
| 100 mL | ||
| 150 mL | ||
| 250 mL | ||
| a 600 mg of casirivimab and 600 mg of imdevimab are added to the same infusion bag and administered together as a single intravenous infusion. | ||
Casirivimab and imdevimab infusion solution should be administered by a qualified healthcare professional using aseptic technique.
Table 2: Recommended Administration Rate for Casirivimab and Imdevimab for Intravenous Infusion.
| Size of Prefilled 0.9% Sodium Chloride Infusion Bag used | Maximum Infusion Rate | Minimum Infusion Time |
| 50 mLa | 180 mL/hr | 20 minutes |
| 100 mL | 310 mL/hr | 21 minutes |
| 150 mL | 310 mL/hr | 31 minutes |
| 250 mL | 310 mL/hr | 50 minutes |
| a The minimum infusion time for patients administered casirivimab and imdevimab together using the 50 mL prefilled 0.9% Sodium Chloride infusion bag must be at least 20 minutes to ensure safe use. | ||
Remove the casirivimab and imdevimab vial(s) from refrigerated storage and allow to equilibrate to room temperature for approximately 20 minutes before preparation. Do not expose to direct heat. Do not shake the vials.
Inspect casirivimab and imdevimab vial(s) visually for particulate matter and discoloration prior to administration. Should either be observed, the vial must be discarded and replaced with a new vial. The solution for each vial should be clear to slightly opalescent, colorless to pale yellow.
Table 3: Preparation of 600 mg of Casirivimab and 600 mg of Imdevimab for Subcutaneous Injections
| Prepare 600 mg of Casirivimab and 600 mg of Imdevimab | Preparation of 4 Syringes |
| Using Casirivimab and Imdevimab Co-formulated Vial | Withdraw 2.5 mL solution per syringe into FOUR separate syringes. |
| Using Casirivimab and Imdevimab Individual Vials |
|
REGEN-COV (casirivimab and imdevimab) is available as:
Co-formulated casirivimab and imdevimab injection is a sterile, preservative-free, clear to slightly opalescent, colorless to pale yellow solution supplied in a single-dose vial. Refer to Table 8.
Casirivimab injection is a sterile, preservative-free, clear to slightly opalescent, colorless to pale yellow solution supplied in a single-dose vial. Refer to Table 9.
Imdevimab injection is a sterile, preservative-free, clear to slightly opalescent, colorless to pale yellow solution supplied in a single-dose vial. Refer to Table 9.
REGEN-COV (casirivimab and imdevimab) injection is available as:
Table 8: Co-Formulated Casirivimab and Imdevimab
| Antibody | Concentration | Package Size | NDC Number |
| REGEN-COV (casirivimab and imdevimab) | 600 mg/600 mg per 10 mL (60 mg/60 mg per mL) | 1 vial per carton | 61755-039-01 |
INDIVIDUAL CASIRIVIMAB AND IMDEVIMAB SOLUTIONS MUST BE ADMINISTERED TOGETHER.
Table 9: Individual Package Size
| Antibody | Concentration | Package Size | NDC Number |
| Casirivimab REGN10933 | 1,332 mg/11.1 mL (120 mg/mL) | 1 vial per carton | 61755-024-01 |
| 300 mg/2.5 mL (120 mg/mL) | 1 vial per carton | 61755-026-01 | |
| Imdevimab REGN10987 | 1,332 mg/11.1 mL (120 mg/mL) | 1 vial per carton | 61755-025-01 |
| 300 mg/2.5 mL (120 mg/mL) | 1 vial per carton | 61755-027-01 |
Each REGEN-COV dose pack contains sufficient number of vials of casirivimab [REGN10933] and imdevimab [REGN10987] to prepare up to two treatment doses (600 mg of casirivimab and 600 mg of imdevimab). Refer to Table 10.
Table 10: Dose Pack Providing 1,200 mg Casirivimab and 1,200 mg Imdevimab
| Dose Pack Size | Dose Pack Components | Concentration | Dose Pack NDC Number |
| 2 Cartons | 1 casirivimab REGN10933 (NDC 61755-024-01) | 1,332 mg/11.1 mL (120 mg/mL) | 61755-035-02 |
| 1 imdevimab REGN10987 (NDC 61755-025-01) | 1,332 mg/11.1 mL (120 mg/mL) | ||
| 8 Cartons | 4 casirivimab REGN10933 (NDC 61755-026-01) | 300 mg/2.5 mL (120 mg/mL) | 61755-036-08 |
| 4 imdevimab REGN10987 (NDC 61755-027-01) | 300 mg/2.5 mL (120 mg/mL) | ||
| 5 Cartons | 1 casirivimab REGN10933 (NDC 61755-024-01) | 1,332 mg/11.1 mL (120 mg/mL) | 61755-037-05 |
| 4 imdevimab REGN10987 (NDC 61755-027-01) | 300 mg/2.5 mL (120 mg/mL) | ||
| 5 Cartons | 4 casirivimab REGN10933 (NDC 61755-026-01) | 300 mg/2.5 mL (120 mg/mL) | 61755-038-05 |
| 1 imdevimab REGN10987 (NDC 61755-025-01) | 1,332 mg/11.1 mL (120 mg/mL) |
Casirivimab is preservative-free. Discard any unused portion.
Imdevimab is preservative-free. Discard any unused portion.
Store unopened casirivimab and imdevimab vials in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.
DO NOT FREEZE. DO NOT SHAKE. DO NOT EXPOSE TO DIRECT LIGHT.
Solution in vial requires dilution prior to administration. The prepared infusion solution is intended to be used immediately. If immediate administration is not possible, store diluted casirivimab and imdevimab solution in the refrigerator at 2°C to 8°C (36°F to 46°F) for no more than 36 hours or at room temperature up to 25°C (77°F) for no more than 4 hours. If refrigerated, allow the infusion solution to equilibrate to room temperature for approximately 30 minutes prior to administration.
The prepared syringes should be administered immediately. If immediate administration is not possible, store the prepared casirivimab and imdevimab syringes in the refrigerator between 2°C to 8°C (36°F to 46°F) for no more than 4 hours or at room temperature up to 25°C (77°F) for no more than 4 total hours. If refrigerated, allow the syringes to equilibrate to room temperature for approximately 20 minutes prior to administration.
Manufactured by: Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591-6707. Revised: Jun 2021
Clinical trials evaluating the safety of REGEN-COV (casirivimab and imdevimab) are ongoing [see Overall Safety Summary ].
Completion of an FDA MedWatch Form to report all medication errors and serious adverse events* occurring during REGEN-COV use and considered to be potentially related to REGEN-COV is mandatory and must be done by the prescribing healthcare provider and/or the provider's designee. These adverse events must be reported within 7 calendar days from the onset of the event:
*Serious Adverse Events are defined as:
If a serious and unexpected adverse event occurs and appears to be associated with the use of REGEN-COV, the prescribing health care provider and/or the provider's designee should complete and submit a MedWatch form to FDA using one of the following methods:
IMPORTANT: When reporting adverse events or medication errors to MedWatch, please complete the entire form with detailed information. It is important that the information reported to FDA be as detailed and complete as possible. Information to include:
The following steps are highlighted to provide the necessary information for safety tracking:
Healthcare facilities and providers must report therapeutics information and utilization data through HHS Protect, Teletracking or National Healthcare Safety Network (NHSN) as directed by the U.S. Department of Health and Human Services.
In addition, please provide a copy of all FDA MedWatch forms to:
Regeneron Pharmaceuticals, Inc
Fax: 1-888-876-2736
E-mail: [email protected]
Or call Regeneron Pharmaceuticals at 1-844-734-6643 to report adverse events.
REGEN-COV consists of 2 monoclonal antibodies (mAbs), casirivimab and imdevimab, which are not renally excreted or metabolized by cytochrome P450 enzymes; therefore, interactions with concomitant medications that are renally excreted or that are substrates, inducers, or inhibitors of cytochrome P450 enzymes are unlikely.
Included as part of the PRECAUTIONS section.
There are limited clinical data available for REGEN-COV (casirivimab and imdevimab). Serious and unexpected adverse events may occur that have not been previously reported with REGEN-COV use.
Serious hypersensitivity reactions, including anaphylaxis, have been reported with administration of REGEN-COV (casirivimab and imdevimab). If signs or symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue administration and initiate appropriate medications and/or supportive care.
Infusion-related reactions, occurring during the infusion and up to 24 hours after the infusion, have been observed with administration of REGEN-COV. These reactions may be severe or life threatening.
Signs and symptoms of infusion related reactions may include:
If an infusion-related reaction occurs, consider slowing or stopping the infusion and administer appropriate medications and/or supportive care.
Hypersensitivity reactions occurring more than 24 hours after the infusion have also been reported with the use of REGEN-COV under Emergency Use Authorization.
Clinical worsening of COVID-19 after administration of REGEN-COV has been reported and may include signs or symptoms of fever, hypoxia or increased respiratory difficulty, arrythmia (e.g., atrial fibrillation, tachycardia, bradycardia), fatigue, and altered mental status. Some of these events required hospitalization. It is not known if these events were related to REGEN-COV use or were due to progression of COVID-19.
Benefit of treatment with REGEN-COV (casirivimab and imdevimab) has not been observed in patients hospitalized due to COVID-19. Monoclonal antibodies, such as REGEN-COV, may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high flow oxygen or mechanical ventilation. Therefore, REGEN-COV is not authorized for use in patients [see Limitations of Authorized Use]:
Overall, more than 9,000 subjects have been exposed to intravenous REGEN-COV (casirivimab and imdevimab) in clinical trials in hospitalized and non-hospitalized subjects.
The safety of REGEN-COV (casirivimab and imdevimab) is based on analyses from, COV-2067, a Phase 1/2/3 trial of 6,311 ambulatory (non-hospitalized) subjects with COVID-19. This is a randomized, double-blind, placebo-controlled clinical trial in subjects with mild to moderate COVID-19 who had a sample collected for the first positive SARS-CoV-2 viral infection determination within 3 days prior to the start of the infusion. In the phase 3 portion of the trial, subjects were treated with a single intravenous infusion of 600 mg of casirivimab and 600 mg of imdevimab (n=827), or 1,200 mg of casirivimab and 1,200 mg of imdevimab (n=1,849), or 4,000 mg of casirivimab and 4,000 mg of imdevimab (n=1,012), or placebo (n=1,843). REGEN-COV is not authorized at the 4,000 mg of casirivimab and 4,000 mg of imdevimab dose. The 1,200 mg of casirivimab and 1,200 mg of imdevimab is no longer authorized under this EUA [see Clinical Trial Results and Supporting Data for EUA (18)].
In pooled phase 1/2/3 analysis, infusion-related reactions (adverse event assessed as causally related by the investigator) of grade 2 or higher severity have been observed in 10/4,206 (0.2%) of those who received REGEN-COV at the authorized dose or a higher dose [see WARNINGS AND PRECAUTIONS].
Overall, in Phase 1/2/3, three subjects receiving the 8,000 mg dose of REGEN-COV, and one subject receiving the 1,200 mg of casirivimab and 1,200 mg of imdevimab infusion-related reactions (urticaria, pruritus, flushing, pyrexia, shortness of breath, chest tightness, nausea, vomiting, rash) which resulted in permanent discontinuation of the infusion. All events resolved [see WARNINGS AND PRECAUTIONS].
Anaphylactic reactions have been reported in the clinical program in subjects receiving REGEN-COV. The events began within 1 hour of completion of the infusion, and in at least one case required treatment including epinephrine. The events resolved.
The safety with subcutaneous administration is based on analysis from HV-2093, a randomized double-blind, placebo-controlled trial evaluating the safety and pharmacokinetic profile in healthy volunteer adult subjects. Subjects were randomized 3:1 to REGEN-COV (n=729) or placebo (n=240). Injection site reactions were observed in 12% and 4% of subjects following single dose administration in the casirivimab and imdevimab, and placebo arms respectively; the remaining safety findings with subcutaneous administration in the casirivimab and imdevimab arm were similar to the safety findings observed with intravenous administration in COV-2067.
Clinically monitor patients during infusion and observe patients for at least 1 hour after intravenous infusion or subcutaneous dosing is complete [see WARNINGS AND PRECAUTIONS and Clinical Trials Experience].
There are insufficient data to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. REGEN-COV (casirivimab and imdevimab) should only be used during pregnancy if the potential benefit outweighs the potential risk for the mother and the fetus.
Nonclinical reproductive toxicity studies have not been conducted with casirivimab and imdevimab. In a tissue cross-reactivity study with casirivimab and imdevimab using human fetal tissues, no binding of clinical concern was detected. Human immunoglobulin G1 (IgG1) antibodies are known to cross the placental barrier; therefore, casirivimab and imdevimab have the potential to be transferred from the mother to the developing fetus. It is unknown whether the potential transfer of casirivimab and imdevimab provides any treatment benefit or risk to the developing fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
There are no available data on the presence of casirivimab and/or imdevimab in human milk or animal milk, the effects on the breastfed infant, or the effects of the drug on milk production. Maternal IgG is known to be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for REGEN-COV (casirivimab and imdevimab) and any potential adverse effects on the breastfed child from REGEN-COV or from the underlying maternal condition. Breastfeeding individuals with COVID-19 should follow practices according to clinical guidelines to avoid exposing the infant to COVID-19.
REGEN-COV is not authorized for use in pediatric patients under 12 years of age or weighing less than 40 kg. The safety and effectiveness of casirivimab and imdevimab are being assessed in pediatric and adolescent patients in an ongoing clinical trial. The recommended dosing regimen is expected to result in comparable serum exposures of casirivimab and imdevimab in patients 12 years of age and older and weighing at least 40 kg as observed in adults, since adults with similar body weight have been included in Trials COV-2067 and HV-2093.
Of the 4,567 subjects with SARS-CoV-2 infection randomized in Trial COV-2067, 14% were 65 years or older, and 4% were 75 years of age or older. Of the 974 subjects randomized in Trial HV-2093, 13% were 65 years or older and 2% were 75 years of age or older. The difference in pharmacokinetics (PK) of casirivimab and imdevimab in geriatric patients compared to younger patients is unknown [see Clinical Trial Results and Supporting Data for EUA].
Casirivimab and imdevimab are not eliminated intact in the urine, thus renal impairment is not expected to affect the exposure of casirivimab and imdevimab.
The effect of hepatic impairment on PK of casirivimab and imdevimab is unknown.
The effect of other covariates (e.g., sex, race, body weight, disease severity) on PK of casirivimab and imdevimab is unknown.
Doses up to 8,000 mg (4,000 mg each of casirivimab and imdevimab, greater than 3 times the recommended dose) have been administered in clinical trials without dose-limiting toxicity. Treatment of overdose should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for overdose with REGEN-COV (casirivimab and imdevimab).
None.
Casirivimab (IgG1κ) and imdevimab (IgG1λ) are two recombinant human mAbs which are unmodified in the Fc regions. Casirivimab and imdevimab bind to non-overlapping epitopes of the spike protein receptor binding domain (RBD) of SARS-CoV-2 with dissociation constants K15D = 45.8 pM and 46.7 pM, respectively. Casirivimab, imdevimab and casirivimab and imdevimab together blocked RBD binding to the human ACE2 receptor with IC50 values of 56.4 pM, 165 pM and 81.8 pM, respectively [see Microbiology/Resistance Information].
Trial COV-2067 evaluated REGEN-COV (casirivimab and imdevimab) with doses of up to 6.66 times the recommended dose (600 mg of casirivimab and 600 mg of imdevimab; 1,200 mg of casirivimab and 1,200 mg of imdevimab; 4,000 mg of casirivimab and 4,000 mg of imdevimab) in ambulatory patients with COVID-19. A flat dose-response relationship for efficacy was identified for REGEN-COV at all doses, based on viral load and clinical outcomes. Similar reductions in viral load (log10 copies/mL) were observed in subjects for the (600 mg of casirivimab and 600 mg of imdevimab) intravenous and (600 mg of casirivimab and 600 mg of imdevimab) subcutaneous doses; however, only limited clinical outcome data are available for the subcutaneous route of administration for the treatment of symptomatic patients.
Both casirivimab and imdevimab exhibited linear and dose-proportional pharmacokinetics (PK) between (600 mg of casirivimab and 600 mg of imdevimab) to (4,000 mg of casirivimab and 4,000 mg of imdevimab) doses of REGEN-COV (casirivimab and imdevimab) following intravenous administration of single dose. A summary of PK parameters after a single (600 mg of casirivimab and 600 mg of imdevimab) intravenous dose, for each antibody is provided in Table 4.
Table 4: Summary of PK Parameters for Casirivimab and Imdevimab After a Single 600 mg of Casirivimab and 600 mg of Imdevimab Intravenous Dose of REGEN-COV in Study COV-2067
| PK Parameter1 | Casirivimab | Imdevimab |
| Ceoi (mg/L)2 | 192 (80.9) | 198 (84.8) |
| C28 (mg/L)3 | 46.2 (22.3) | 38.5 (19.7) |
| 1 Mean (SD) 2 concentration at end of 1-hour infusion 3 observed concentration 28 days after dosing, i.e., on day 29, as defined in the protocol |
||
A summary of PK parameters after a single 600 mg of casirivimab and 600 mg of imdevimab subcutaneous dose is shown in Table 5.
Table 5: Summary of PK Parameters for Casirivimab and Imdevimab After a Single 600 mg of Casirivimab and 600 mg of Imdevimab Subcutaneous Dose of REGEN-COV
| PK Parameter1,5 | Casirivimab | Imdevimab |
| Cmax (mg/L) | 55.6 (22.2) | 52.7 (22.5) |
| tmax (day)2 | 8.00 (4.00, 87.0) | 7.00 (4.00, 15.0) |
| AUC0-28 (mg•day/L) | 1060(363) | 950 (362) |
| AUCinf (mg•day/L)3 | 2580 ( 1349) | 1990 (1141) |
| C28 (mg/L)4 | 30.7 ( 11.9) | 24.8 (9.58) |
| Half-life (day) | 31.8 (8.35) | 26.9 (6.80) |
| 1 Mean (SD) 2 Median (range) 3 Value reported for subjects with %AUCinf extrapolated <20% 4 Observed concentration 28 days after dosing, i.e., on day 29 5 Mean (SD) concentration at 24 hours (C24) of casirivimab and imdevimab in serum with 1200 SC dosing, 22.5 (11.0) mg/L and 25.0 (16.4) mg/L, respectively |
||
The effect of different covariates (e.g., age, sex, race, body weight, disease severity, hepatic impairment) on the PK of casirivimab and imdevimab is unknown. Renal impairment is not expected to impact the PK of casirivimab and imdevimab, since mAbs with molecular weight >69 kDa are known not to undergo renal elimination. Similarly, dialysis is not expected to impact the PK of casirivimab and imdevimab.
Casirivimab and imdevimab are mAbs which are not renally excreted or metabolized by cytochrome P450 enzymes; therefore, interactions with concomitant medications that are renally excreted or that are substrates, inducers, or inhibitors of cytochrome P450 enzymes are unlikely [see DRUG INTERACTIONS].
In a SARS-CoV-2 virus neutralization assay in Vero E6 cells, casirivimab, imdevimab, and casirivimab and imdevimab together neutralized SARS-CoV-2 (USA-WA1/2020 isolate) with EC50 values of 37.4 pM (0.006 μg/mL), 42.1 pM (0.006 μg/mL), and 31.0 pM (0.005 μg/mL) respectively.
Antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) were assessed using Jurkat target cells expressing SARS-CoV-2 spike protein. Casirivimab, imdevimab and casirivimab and imdevimab together mediated ADCC with human natural killer (NK) effector cells. Casirivimab, imdevimab and casirivimab and imdevimab together mediated ADCP with human macrophages. Casirivimab, imdevimab and casirivimab and imdevimab together did not mediate complement-dependent cytotoxicity in cell-based assays.
The potential of casirivimab and of imdevimab to mediate viral entry was assessed in immune cell lines co-incubated with recombinant vesicular stomatitis virus (VSV) virus-like particles (VLP) pseudotyped with SARS-CoV-2 spike protein at concentrations of mAb(s) down to approximately 10-fold below the respective neutralization EC50 values. Casirivimab and imdevimab together and imdevimab alone, but not casirivimab alone, mediated entry of pseudotyped VLP into FcγR2+ Raji and FcγR1+/FcγR2+ THP1 cells (maximum infection in total cells of 1.34% and 0.24%, respectively, for imdevimab; 0.69% and 0.06%, respectively for casirivimab and imdevimab together), but not any other cell lines tested (IM9, K562, Ramos and U937 cells).
There is a potential risk of treatment failure due to the development of viral variants that are resistant to casirivimab and imdevimab administered together. Prescribing healthcare providers should consider the prevalence of SARS-CoV-2 variants in their area, where data are available, when considering treatment options.
Escape variants were identified following two passages in cell culture of recombinant VSV encoding SARS-CoV-2 spike protein in the presence of casirivimab or imdevimab individually, but not following two passages in the presence of casirivimab and imdevimab together. Variants which showed reduced susceptibility to casirivimab alone included those with spike protein amino acid substitutions K417E (182-fold), K417N (7-fold), K417R (61-fold), Y453F (>438-fold), L455F (80-fold), E484K (25-fold), F486V (>438-fold) and Q493K (>438-fold). Variants which showed reduced susceptibility to imdevimab alone included substitutions K444N (>755-fold), K444Q (>548-fold), K444T (>1,033-fold), and V445A (548-fold). Casirivimab and imdevimab together showed reduced susceptibility to variants with K444T (6-fold) and V445A (5-fold) substitutions.
In neutralization assays using VSV VLP pseudotyped with spike protein variants identified in circulating SARS-CoV-2, variants with reduced susceptibility to casirivimab alone included those with E406D (51-fold), V445T (107-fold), E484Q (19-fold), G485D (5-fold), G476S (5-fold), F486L (61-fold), F486S (>715-fold), Q493E (446-fold), Q493R (70-fold), and S494P (5-fold) substitutions, and variants with reduced susceptibility to imdevimab alone included those with P337L (5-fold), N439K (463-fold), N439V (4-fold), N440K (28-fold), K444L (153-fold), K444M (1,577-fold), G446V (135-fold), N450D (9-fold), Q493R (5-fold), Q498H (17-fold), P499S (206-fold) substitutions. The G476D substitution had an impact (4-fold) on casirivimab and imdevimab together.
Casirivimab and imdevimab individually and together retained neutralization activity against pseudotyped VLP expressing all spike protein substitutions found in the B.1.1.7 lineage (UK origin) and against pseudotyped VLP expressing only N501Y found in B.1.1.7 and other circulating lineages (Table 6). Casirivimab and imdevimab together retained neutralization activity against pseudotyped VLP expressing all spike protein substitutions, or individual substitutions K417N, E484K or N501Y, found in the B.1.1351 lineage (South Africa origin), and all spike protein substitutions or key substitutions K417T+E484K, found in the P.1 lineage (Brazil origin), although casirivimab alone, but not imdevimab, had reduced activity against pseudotyped VLP expressing K417N or E484K, as indicated above. The E484K substitution is also found in the B.1.526 lineage (New York origin). Casirivimab and imdevimab, individually and together, retained neutralization activity against the L452R substitution found in the B.1.427/B.1.429 lineages (California origin). Casirivimab and imdevimab, individually and together, retained neutralization activity against pseudotyped VLP expressing L452R+K478T substitutions found in the B.1.617.2 lineage (India origin). Casirivimab and imdevimab together retained neutralization activity against pseudotyped VLP expressing L452R+E484Q substitutions, found in the B.1.617.1/B.1.617.3 lineages (India origin), although casirivimab alone, but not imdevimab, had reduced activity against pseudotyped VLP expressing E484Q, as indicated above.
Table 6: Pseudotyped Virus-Like Particle Neutralization Data for SARS-CoV-2 Variant Substitutions with Casirivimab and Imdevimab Together
| Lineage with Spike Protein Substitution | Key Substitutions Tested | Fold Reduction in Susceptibility |
| B.1.1.7 (UK origin) | N501Ya | no changed |
| B.1.351 (South Africa origin) | K417N, E484K, N501Yb | no changed |
| P.1 (Brazil origin) | K417T + E484Kc | no changed |
| B.1.427/B.1.429 (California origin) | L452R | no changed |
| B.1.526 (New York origin)6 | E484K | no changed |
| B.1.617.1/B.1.617.3 (India origin) | L452R+E484Q | no changed |
| B.1.617.2 (India origin) | L452R+K478T | no changed |
| a Pseudotyped VLP expressing the entire variant spike protein was tested. The following changes from wild-type spike protein are found in the variant: del69-70, del145, N501Y, A570D, D614G, P681H, T716I, S982A, D1118H. b Pseudotyped VLP expressing the entire variant spike protein was tested. The following changes from wild-type spike protein are found in the variant: D80Y, D215Y, del241-243, K417N, E484K, N501Y, D614G, A701V. c Pseudotyped VLP expressing the entire variant spike protein was tested. The following changes from wild-type spike protein are found in the variant: L18F, T20N, P26S, D138Y, R190S, K417T, E484K, N501Y, D614G, H655Y, T1027I, V1176F d No change: ≤2-fold reduction in susceptibility. e Not all isolates of the New York lineage harbor the E484K substitution (as of February 2021). |
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It is not known how pseudotyped VLP data correlate with clinical outcomes.
In clinical trial COV-2067, interim data indicated only one variant (G446V) occurring at an allele fraction ≥15%, which was detected in 3/66 subjects who had nucleotide sequencing data, each at a single time point (two at baseline in subjects from placebo and 2,400 mg casirivimab and imdevimab groups, and one at Day 25 in a subject from the 8,000 mg casirivimab and imdevimab group). The G446V variant had reduced susceptibility to imdevimab of 135-fold compared to wild-type in a pseudotyped VSV VLP neutralization assay but retained susceptibility to casirivimab alone and casirivimab and imdevimab together.
It is possible that resistance-associated variants to casirivimab and imdevimab together could have cross-resistance to other mAbs targeting the receptor binding domain of SARS-CoV-2. The clinical impact is not known.
There is a theoretical risk that antibody administration may attenuate the endogenous immune response to SARS-CoV-2 and make patients more susceptible to re-infection.
Carcinogenicity, genotoxicity, and reproductive toxicology studies have not been conducted with casirivimab and imdevimab.
In a toxicology study in cynomolgus monkeys, casirivimab and imdevimab had no adverse effects when administered intravenously. Non-adverse liver findings (minor transient increases in AST and ALT) were observed.
In tissue cross-reactivity studies with casirivimab and imdevimab using human adult and fetal tissues, no binding of clinical concern was detected.
Casirivimab and imdevimab administered together has been assessed in rhesus macaque and Syrian golden hamster treatment models of SARS-CoV-2 infection. Therapeutic administration of casirivimab and imdevimab together at 25 mg/kg or 150 mg/kg into rhesus macaques (n=4 for each dosing group) 1-day post infection resulted in approximately 1-2 log10 reductions in genomic and sub-genomic viral RNA in nasopharyngeal swabs and oral swabs at Day 4 post-challenge in most animals, and reduced lung pathology relative to placebo-treated animals. Therapeutic administration of casirivimab and imdevimab together at 5 mg/kg and 50 mg/kg doses to hamsters 1-day post infection resulted in reduced weight loss relative to placebo treated animals, but had no clear effects on viral load in lung tissue. The applicability of these findings to a clinical setting is not known.
The data supporting this EUA are based on the analysis of Phase 1/2/3 from trial, COV-2067 (NCT04425629). This is a randomized, double-blinded, placebo-controlled clinical trial evaluating REGEN-COV (casirivimab and imdevimab) for the treatment of subjects with mild to moderate COVID-19 (subjects with COVID-19 symptoms who are not hospitalized). Cohort 1 enrolled adult subjects who were not hospitalized and had 1 or more COVID-19 symptoms that were at least mild in severity. Treatment was initiated within 3 days of obtaining a positive SARS-CoV-2 viral infection determination. Subjects in the Phase 3 primary efficacy analysis met the criteria for high risk for progression to severe COVID-19, as shown in Section 2.
In the Phase 3 trial, 4,567 subjects with at least one risk factor for severe COVID-19 were randomized to a single intravenous infusion of 600 mg of casirivimab and 600 mg of imdevimab (n=838), 1,200 mg of casirivimab and 1,200 mg of imdevimab (n=1,529), 4,000 mg of casirivimab and 4,000 mg of imdevimab (n=700), or placebo (n=1,500) groups. The two REGEN-COV doses at the start of Phase 3 were 4,000 mg and 1,200 mg of each component; however, based on Phase 1/2 efficacy analyses showing that the 4,000 mg and 1,200 mg doses of each component were similar, the Phase 3 portion of the protocol was amended to compare 1,200 mg dose of each component vs. placebo and 600 mg dose of each component vs. placebo. Comparisons were between subjects randomized to the specific REGEN-COV dose and subjects who were concurrently randomized to placebo.
At baseline, in all randomized subjects with at least one risk factor, the median age was 50 years (with 13% of subjects ages 65 years or older), 52% of the subjects were female, 84% were White, 36% were Hispanic or Latino, and 5% were Black or African American. In subjects with available baseline symptom data, 15% had mild symptoms, 42% had moderate, 42% had severe symptoms, and 2% reported no symptoms at baseline; the median duration of symptoms was 3 days; mean viral load was 6.2 log10 copies/mL at baseline. The baseline demographics and disease characteristics were well balanced across the casirivimab and imdevimab and placebo treatment groups.
The primary endpoint was the proportion of subjects with ≥1 COVID-19-related hospitalization or all-cause death through Day 29, in subjects with a positive SARS-CoV-2 RT-qPCR result from nasopharyngeal (NP) swab at randomization, and with at least one risk factor for severe COVID-19, i.e., the modified full analysis set (mFAS). In the mFAS, events (COVID-19-related hospitalization or all-cause death through Day 29) occurred in 7 (1.0%) subjects treated with 600 mg of casirivimab and 600 mg of imdevimab compared to 24 (3%) subjects concurrently randomized to placebo, demonstrating a 70% reduction in COVID-19-related hospitalization or all-cause death compared to placebo (p=0.0024). Events occurred in 18 (1.3%) subjects treated with 1,200 mg of casirivimab and 1,200 mg of imdevimab compared to 62 (5%) subjects concurrently randomized to placebo, demonstrating a 71% reduction compared to placebo (REGEN-COV 1% vs placebo 5%, p<0.0001). In the 1,200 mg analysis, there was 1 death each in the REGEN-COV and placebo arm (p=1.0); and in 2,400 mg analysis, there were 1 and 3 deaths, respectively, in the REGEN-COV and placebo arms (p=0.3721). Overall, similar effects were observed for 600 mg of casirivimab and 600 mg of imdevimab and 1,200 mg of casirivimab and 1,200 mg of imdevimab doses, indicating the absence of a dose effect; therefore the 600 mg of casirivimab and 600 mg of imdevimab dose is authorized and the 1,200 mg of casirivimab and 1,200 mg of imdevimab dose is no longer authorized under this EUA (See Table 7). Results were consistent across subgroups of patients defined by nasopharyngeal viral load >106 copies/mL at baseline or serologic status.
Table 7: Proportion of subjects with ≥1 COVID-19-related hospitalization or all-cause death through day 29
| 600 mg of casirivimab and 600 mg of imdevimab (intravenous) n=736 |
Placebo n=748 |
1,200 mg of casirivimab and 1,200 mg of imdevimab (intravenous) n=1,355 |
Placebo n=1,341 |
|
| # of subjects with at least 1 event (COVID-19-related hospitalization or allcause death) | 7 (1.0%) | 24 (3.2%) | 18 (1.3%) | 62 (4.6%) |
| Risk reduction | 70% (p=0.0024) | 71% (p<0.0001) | ||
Treatment with REGEN-COV resulted in a statistically significant reduction in the LS mean viral load (log10 copies/mL) from baseline to Day 7 compared to placebo (-0.71 log10 copies/mL for 600 mg dose of casirivimab and 600 mg of imdevimab and -0.86 log10 copies/mL for 2,400 mg; p<0.0001). Reductions were observed in the overall mFAS population and in other subgroups, including those with baseline viral load >106 copies/mL or who were seronegative at baseline. Consistent effects were observed for the individual doses, indicating the absence of a dose effect. shows the mean change from baseline in SARS-COV-2 viral load to Day 15.
Figure 1: Change from Baseline in SARS-COV-2 Viral Load (log10 copies/mL) to Day 15
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The median time to symptom resolution, as recorded in a trial-specific daily symptom diary, was 10 days for REGEN-COV-treated subjects, as compared with 14 days for placebo-treated subjects (p=0.0001 for 600 mg of casirivimab and 600 mg of imdevimab vs. placebo; p<0.0001 for 1,200 mg of casirivimab and 1,200 mg of imdevimab vs. placebo). Symptoms assessed were fever, chills, sore throat, cough, shortness of breath/difficulty breathing, nausea, vomiting, diarrhea, headache, red/watery eyes, body aches, loss of taste/smell, fatigue, loss of appetite, confusion, dizziness, pressure/tight chest, chest pain, stomachache, rash, sneezing, sputum/phlegm, runny nose. Time to COVID-19 symptom resolution was defined as time from randomization to the first day during which the subject scored ‘no symptom’ (score of 0) on all of the above symptoms except cough, fatigue, and headache, which could have been ‘mild/moderate symptom’ (score of 1) or ‘no symptom’ (score of 0).
Patients treated with REGEN-COV (casirivimab and imdevimab) should continue to self-isolate and use infection control measures (e.g., wear mask, isolate, social distance, avoid sharing personal items, clean and disinfect “high touch” surfaces, and frequent handwashing) according to CDC guidelines. Also see Fact Sheet for Patients, Parents and Caregivers.
For additional information visit www.REGENCOV.com
If you have questions, please contact Regeneron at 1-844-734-6643.
