REGEN-COV™ (casirivimab with imdevimab)

REGEN-COV (casirivimab with imdevimab to be administered together) has not been approved, but has been authorized for emergency use by FDA, 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 progressing to severe COVID-19 and/or hospitalization.

This use is authorized only for the duration of the declaration that circumstances exist justifying the authorization of the emergency use under section 564(b)(1) of the Food Drug and Cosmetic Act, unless the authorization is terminated or revoked sooner.

Clinical Trial Results and Supporting Data for EUA

The data supporting this EUA are based on the analysis of Phase 1/2 from Study 1, that occurred after 799 enrolled subjects in Phase 1/2 had completed at least 28 days of study duration. Study 1 is a randomized, double-blinded, placebo-controlled clinical trial studying REGEN-COV (casirivimab with imdevimab) for the treatment of adult subjects with mild to moderate COVID-19 (subjects with COVID-19 symptoms who are not hospitalized). The trial enrolled adult subjects who were not hospitalized and had at least 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 were randomized in a 1:1:1 manner to receive a single intravenous (IV) infusion of 2,400 mg of REGEN-COV (1,200 mg of casirivimab and 1,200 mg of imdevimab) (n=266), or 8,000 mg of REGEN-COV (4,000 mg of casirivimab and 4,000 mg of imdevimab) (n=267), or placebo (n=266).

At baseline, the median age was 42 years (with 7% of subjects ages 65 years or older), 53% of the subjects were female, 85% were White, 50% were Hispanic or Latino, and 9% were Black; 34% were considered high risk (as defined below). Approximately 31% of subjects reported at least 1 severe symptom at baseline, 36% reported at least 1 moderate symptom and no severe symptoms, and 13% reported only mild symptoms. The median duration of symptoms was 3 days; mean viral load was 5.8 log₁₀ copies/mL at baseline. The baseline demographics and disease characteristics were well balanced across the REGEN-COV and placebo treatment groups.

The pre-specified primary endpoint in Phase 1/2 of trial Study 1 was the time weighted average (TWA) change from baseline in viral load (log₁₀ copies/mL), as measured by RT-qPCR in nasopharyngeal swab samples, in subjects with a positive baseline RT-qPCR value, i.e., the modified full analysis set (mFAS), see Figure 1. In the mFAS for the Phase 1/2 analysis, the difference in TWA from Day 1 through Day 7 for the pooled doses of REGEN-COV compared with placebo (n=665) was -0.36 log₁₀ copies/mL (p<0.0001). The largest reductions in viral load relative to placebo occurred in patients with high viral load (-0.78 log₁₀ copies /mL) or who were seronegative (-0.69 log₁₀ copies /mL) at baseline. Reductions occurring from Day 1 through Day 11 were similar to those for Day 1 through Day 7. Figure 1 (below) shows the mean change from baseline in SARS-COV-2 viral load over time.

Figure 1. Mean Change from Baseline in SARS-COV-2 Viral Load Over Time

While viral load was used to define the primary endpoint in the Phase 1/2 analysis, clinical evidence demonstrating that REGEN-COV may be effective came from the predefined secondary endpoint, medically attended visits (MAV) related to COVID-19. Medically attended visits comprised hospitalizations, emergency room visits, urgent care visits, or physician office/telemedicine visits for COVID-19. A lower proportion of subjects treated with REGEN-COV had COVID-19 related MAVs (2.8% for combined treatment arms vs 6.5% placebo). In post-hoc analyses, a lower proportion of subjects treated with REGEN-COV had COVID-19-related hospitalizations or emergency room visits compared to placebo, see Table 3. Results for this endpoint were suggestive of a relatively flat dose-response relationship. The absolute risk reduction for REGEN-COV compared to placebo was greater in subjects at high risk for progression to severe COVID-19 and/or hospitalization, according to the high risk criteria (defined below) (Table 4).

Table 3: Proportion of Subjects with Events of Hospitalization or Emergency Room Visits Within 28 Days After Treatment^a

Treatment	N^b	Events	Proportion of subjects
Placebo	231	10	4%
2,400 mg^c REGEN-COV	215	4	2%
8,000 mg^d REGEN-COV	219	4	2%
All doses REGEN-COV	434	8	2%

^a Hospitalization and emergency room visits were a subset of a key secondary endpoint, Medically-Attended Visits, which also included urgent care visits, physician’s office visits and telemedicine visits.
^b N = number of randomized subjects with a positive central-lab determined RT-qPCR from nasopharyngeal swab samples at randomization
^c 2,400 mg (1,200 mg casirivimab and 1,200 mg imdevimab)
^d 8,000 mg (4,000 mg casirivimab and 4,000 mg imdevimab)

Table 4: Proportion of Subjects with Events of Hospitalization or Emergency Room Visits Within 28 Days After Treatment for Subjects at Higher Risk of Hospitalization^a

Treatment	N^b	Events	Proportion of subjects
Placebo	78	7	9%
2,400 mg^c REGEN-COV	70	2	3%
8,000 mg^d REGEN-COV	81	2	2%
All doses REGEN-COV	151	4	3%

The median time to symptom improvement as recorded in a trial-specific daily symptom diary, was 5 days for REGEN-COV-treated subjects, as compared with 6 days for placebo-treated subjects. Symptoms assessed were shortness of breath or difficulty breathing, chills, feverish, sore throat, cough, nausea, vomiting, diarrhea, headache, red or watery eyes, body and muscle aches, loss of taste or smell, fatigue, loss of appetite, confusion, dizziness, pressure or tight chest, chest pain, stomach ache, rash, sneezing, sputum/phlegm, runny nose. Symptom improvement was defined as symptoms scored as moderate or severe at baseline being scored as mild or absent, and symptoms scored as mild or absent at baseline being scored as absent.

Publication

Outpatient ambulatory adult patients

Regeneron is working closely with health authorities and is focused on contributing our infectious disease expertise and resources to help patients and communities impacted by COVID-19.

IMPORTANT SAFETY INFORMATION

REGEN-COV (casirivimab with imdevimab) is an unapproved investigational therapy, and there are limited clinical data available. Serious and unexpected adverse events may occur that have not been previously reported with REGEN-COV use.

Warnings and Precautions
- Hypersensitivity Including Anaphylaxis and Infusion-Related Reactions: Serious hypersensitivity reactions, including anaphylaxis, have been observed with administration of REGEN-COV (casirivimab with 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 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: fever, difficulty breathing, reduced oxygen saturation, chills, nausea, arrythmia (e.g., atrial fibrillation, tachycardia, bradycardia), chest pain or discomfort, weakness, altered mental status, headache, bronchospasm, hypotension, hypertension, angioedema, throat irritation, rash including urticaria, pruritus, myalgia, dizziness, fatigue and diaphoresis. If an infusion-related reaction occurs, consider slowing or stopping the infusion and administer appropriate medications and/or supportive care
- Clinical Worsening After REGEN-COV Administration: 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
- Limitations of Benefit and Potential for Risk in Patients with Severe COVID-19: Benefit of treatment with REGEN-COV 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 requiring high-flow oxygen or mechanical ventilation with COVID-19. Therefore, REGEN-COV is not authorized for use in patients who are hospitalized due to COVID-19, OR who require oxygen therapy due to COVID-19, OR who require an increase in baseline oxygen flow rate due to COVID-19 in those on chronic oxygen therapy due to underlying non-COVID-19–related comorbidity
Adverse Reactions:
- Serious adverse events (SAEs) were reported in 4 (1.6%) patients in the REGEN-COV 2,400-mg group, 2 (0.8%) patients in the REGEN-COV 8,000-mg group, and 6 (2.3%) patients in the placebo group. None of the SAEs were considered to be related to study drug. SAEs that were reported as Grade 3 or 4 adverse events were pneumonia, hyperglycemia, nausea and vomiting (2,400 mg REGEN-COV), intestinal obstruction and dyspnea (8,000 mg REGEN-COV) and COVID-19, pneumonia and hypoxia (placebo). REGEN-COV is not authorized at the 8,000-mg dose (4,000 mg casirivimab and 4,000 mg imdevimab)
- One anaphylactic reaction was reported in the clinical program. The event began within 1 hour of completion of the infusion, and required treatment including epinephrine. The event resolved. Infusion-related reactions, of Grade 2 or higher severity, were reported in 4 subjects (1.5%) in the 8,000-mg (4,000 mg casirivimab and 4,000 mg imdevimab) arm. These infusion-related reactions events were moderate in severity; and included pyrexia, chills, urticaria, pruritus, abdominal pain, and flushing. One infusion-related reaction (nausea) was reported in the placebo arm, and none were reported in the 2,400-mg (1,200 mg casirivimab and 1,200 mg imdevimab) arm. In two subjects receiving the 8,000-mg dose of REGEN-COV, the infusion-related reactions (urticaria, pruritus, flushing, pyrexia, shortness of breath, chest tightness, nausea, vomiting) resulted in permanent discontinuation of the infusion. All events resolved.
Patient Monitoring Recommendations: Clinically monitor patients during infusion and observe patients for at least 1 hour after infusion is complete
Use in Specific Populations:
- Pregnancy: There is currently limited clinical experience in the use of REGEN-COV in COVID-19 patients who are pregnant. REGEN-COV therapy should be used during pregnancy only if the potential benefit justifies the potential risk for the mother and the fetus
- Nursing Mothers: There is currently no clinical experience in the use of REGEN-COV in COVID-19 patients who are breastfeeding. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for REGEN-COV and any potential adverse effects on the breastfed child from REGEN-COV or from the underlying maternal condition

AUTHORIZED USE

REGEN-COV (casirivimab with imdevimab to be administered together) is authorized for the treatment of mild to moderate coronavirus disease 2019 (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 progressing to severe COVID-19 and/or hospitalization. [see Limitations of Authorized Use]

REGEN-COV has not been approved, but has been authorized for emergency use by FDA
This use is authorized only for the duration of the declaration that circumstances exist justifying the authorization of the emergency use under section 564(b)(1) of the Act, 21 U.S.C. § 360bbb-3(b)(1), unless the authorization is terminated or revoked sooner
Healthcare providers should review the Fact Sheet for Healthcare Providers for information on the authorized use of REGEN-COV and mandatory requirements of the EUA and must comply with the requirements of the EUA. The FDA Letter of Authorization is available for reference, as well as the Dear Healthcare Provider Letter and Patient Fact Sheet

Limitations of Authorized Use:

REGEN-COV (casirivimab with imdevimab) is not authorized for use in patients:
- who are hospitalized due to COVID-19, OR
- who require oxygen therapy due to COVID-19, OR
- who require an increase in baseline oxygen flow rate due to COVID-19 in those on chronic oxygen therapy due to underlying non-COVID-19 related comorbidity.
Benefit of treatment with REGEN-COV 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

Definition of High Risk Patients

High risk is defined as patients who meet at least one of the following criteria:

Have a body mass index (BMI) ≥35
Have chronic kidney disease
Have diabetes
Have immunosuppressive disease
Are currently receiving immunosuppressive treatment
Are ≥65 years of age
Are ≥55 years of age AND have
- cardiovascular disease, OR
- hypertension, OR
- chronic obstructive pulmonary disease/other chronic respiratory disease
Are 12–17 years of age AND have
- BMI ≥85th percentile for their age and gender based on CDC growth charts, https://www.cdc.gov/growthcharts/clinical_charts.htm, OR
- sickle cell disease, OR
- congenital or acquired heart disease, OR
- neurodevelopmental disorders (e.g. cerebral palsy), OR
- a medical-related technological dependence, for example, tracheostomy, gastrostomy, or positive pressure ventilation (not related to COVID-19), OR
- asthma, reactive airway or other chronic respiratory disease that requires daily medication for control

ADDITIONAL INFORMATION FOR HEALTHCARE PROVIDERS

Casirivimab and imdevimab are each provided in a separate carton and vial. Casirivimab and imdevimab vial labels and carton labeling may instead be labeled REGN10933 and REGN10987, respectively.
Each REGEN-COV dose pack contains sufficient number of vials of casirivimab (REGN10933) and imdevimab (REGN10987) to prepare one treatment dose.
You may receive cartons and vials of casirivimab and imdevimab that are labeled "for intravenous infusion or subcutaneous injection." However, casirivimab and imdevimab must be administered together (although packaged separately) after dilution by intravenous (IV) infusion only
Store casirivimab and imdevimab together in inventory. See www.regeneroneua.com/access for images of packaging
REGEN-COV may only be administered in settings in which healthcare providers have immediate access to medications to treat a severe infusion reaction, such as anaphylaxis, and the ability to activate the emergency medical system (EMS), as necessary
The recommended dose is 1200 mg of casirivimab with 1200 mg of imdevimab administered as a single intravenous infusion over at least 60 minutes as soon as possible after positive results of direct SARS-CoV-2 viral testing and within 10 days of symptom onset. Since the optimal dosing regimen has not yet been established, it might be updated as data become available. See the Fact Sheet for Healthcare Providers for complete dosage, preparation, and administration instructions

The prescribing healthcare provider and/or the provider's designee are responsible for mandatory reporting of all medication errors and ALL SERIOUS ADVERSE EVENTS potentially related to REGEN-COV. These adverse events must be reported within 7 calendar days from the onset of the event
Healthcare facilities and providers must report therapeutics information and demonstrate adequate utilization via data reported through HHS Protect, Teletracking or National Healthcare Safety Network (NHSN) as directed by the U.S. Department of Health and Human Services
MedWatch adverse event reports can be submitted to the FDA here, by using a postage-paid Form FDA 3500 and returning by mail/fax, or by calling 1-800-FDA-1088 to request a reporting form. In addition, please provide a copy of all FDA MedWatch forms to Regeneron Pharmaceuticals, Inc via fax (1-888-876-2736) or email ([email protected]regeneron.com)