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FDA Expands Authorized Use of
REGEN-COV™ (casirivimab and imdevimab)
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TARRYTOWN, N.Y., July 30, 2021 /PRNewswire/ --
Expanded authorization enables use of REGEN-COV for post-exposure prophylaxis in certain people exposed to a SARS-CoV-2 infected individual, or who are at high risk of exposure to an infected individual in an institutional setting
Supported by pivotal Phase 3 data showing 81% reduced risk of symptomatic infections in close contacts of SARS-CoV-2 infected individuals
Only COVID-19 antibody therapy currently available across the U.S. for both treatment and post-exposure prophylaxis; REGEN-COV retains potency against variants of concern
Use of REGEN-COV across the U.S. is rapidly increasing to address ongoing outbreaks
Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) today announced that the U.S. Food and Drug Administration (FDA) updated the Emergency Use Authorization (EUA) for the investigational COVID-19 antibody cocktail REGEN-COV™ (casirivimab and imdevimab). The authorization now includes post-exposure prophylaxis in people at high risk for progression to severe
COVID-19, who are not fully vaccinated or are not expected to mount an adequate response to vaccination, and have been exposed to a SARS-CoV-2 infected individual, or who are at high risk of exposure to an infected individual because of infection occurring in the same institutional setting (such as in nursing homes or prisons).
In those who require repeat dosing for ongoing exposure, REGEN-COV can also now be administered monthly. This new indication in people aged 12 and older is in addition to the previously granted authorization to treat non-hospitalized patients. REGEN-COV is not a substitute for vaccination against COVID-19, and is not authorized for pre-exposure prophylaxis to prevent COVID-19.
"Today's FDA authorization enables certain people at high risk of developing severe COVID-19 infection to access REGEN-COV if they have been exposed to the virus - the first time an antibody treatment has been authorized for this purpose," said George D. Yancopoulos, M.D., Ph.D., President and Chief Scientific Officer of Regeneron. "With this authorization, the FDA specifically highlights the needs of immunocompromised people, including those taking immunosuppressive medicines, who may not mount an adequate response to vaccination, who are exposed to a person with COVID-19 or are in an institutional setting and are at high risk of exposure because of infection occurring in the same setting. Today's FDA decision to expand the use of REGEN-COV in post-exposure settings is a very helpful step, and we continue to work with the FDA as it undertakes its review of REGEN-COV in a broader group of people including in a pre-exposure prophylactic setting for people who are immunocompromised, and in patients hospitalized due to COVID-19."
Experts estimate that approximately 3% of the U.S. population may not respond fully to COVID-19 vaccination because of immunocompromising conditions or immunosuppressive medicines. This includes people receiving chemotherapy, people with hematologic cancers such as chronic lymphocytic leukemia, people receiving stem cells or hemodialysis, people who have received organ transplants, and/or people taking certain medications that might blunt immune response (e.g., mycophenolate, rituximab, azathioprine, anti-CD20 monoclonal antibodies, Bruton tyrosine kinase inhibitors). This authorization enables these groups to use REGEN-COV to prevent infection in post-exposure and certain institutional settings.
Under the EUA for post-exposure prophylaxis, REGEN-COV can be administered by subcutaneous injection or intravenous infusion. For people who aren't expected to mount an adequate immune response to vaccination and who have an ongoing exposure to SARS-CoV-2 for more than four weeks, the initial 1,200 mg dose can be followed by subsequent repeat dosing of REGEN-COV 600 mg once every four weeks, for the duration of ongoing exposure.
REGEN-COV has not been approved by the FDA, but is currently authorized 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.
Multiple analyses, including a recent publication in Cell, have shown that REGEN-COV retains potency against the main variants of concern circulating within the U.S., including Delta (B.1.617.2; first identified in India), Gamma (P.1; first identified in Brazil) and Beta (B.1.351; first identified in South Africa). Consequently, REGEN-COV remains available for use across the U.S., and Regeneron will continue actively monitoring the potency of REGEN-COV against emerging variants.
The development and manufacturing of REGEN-COV have been funded in part with federal funds from the Biomedical Advanced Research and Development Authority (BARDA), part of the U.S. Department of Health and Human Services' Office of the Assistant Secretary for Preparedness and Response, under OT number: HHSO100201700020C.
Regeneron is collaborating with Roche to increase global supply of the antibody cocktail, with Roche primarily responsible for development and distribution outside the U.S. Regeneron and Roche share a commitment to making the antibody cocktail available to COVID-19 patients around the globe and will support access in low- and lower-middle-income countries through drug donations to be made in partnership with public health organizations.
About the Clinical Data Supporting the EUA Extension
The REGEN-COV EUA for post-exposure prophylaxis is based on data from multiple groups.
A pivotal Phase 3 trial jointly run with the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), assessed REGEN-COV for post-exposure prophylaxis of COVID-19 in household contacts of individuals infected with SARS-CoV-2 (index case). REGEN-COV was found to:
• Reduce the risk of symptomatic infections by 81%in those who were not infected when they entered the trial (p<0.0001).
⋅ There were 1,505 participants (753 REGEN-COV, 752 placebo) who were not infected (seronegative with a negative PCR test) when they entered the trial.
⋅ In a post-hoc analysis in the subgroup of participants who met the criteria for high risk for progression to severe COVID-19 (570 REGEN-COV, 567 placebo), there was a 76% risk reduction in COVID-19 with REGEN-COV treatment compared to placebo (p<0.0001).
⋅ Adverse events were reported in 20% (265/1,311) of REGEN-COV participants and 29% (379/1,306) of placebo participants. Injection site reactions (all mild to moderate) occurred in 4% (55) of REGEN-COV participants and 2% (19) of placebo participants. Hypersensitivity reactions occurred in 0.2% (2) of REGEN-COV participants, all of which were mild in severity.
• Reduced the risk of symptomatic infections by 62% in a broader group of asymptomatic participants, regardless of infection status, based on a post-hoc analysis (p<0.0001).
⋅ There were 2,378 participants who were asymptomatic when they entered the trial, regardless of serology (1,201 REGEN-COV, 1,177 placebo).
⋅ Adverse events for uninfected individuals are reported above, and for infected individuals (n=311) were reported in 34% (52/155) of REGEN-COV participants and 48% (75/156) of placebo participants. Injection site reactions (all mild to moderate) occurred in 4% (6) of REGEN-COV participants and 1% (1) of placebo participants. There were no cases of hypersensitivity reaction.
An additional double-blind, placebo-controlled Phase 1 trial evaluated the safety, pharmacokinetic and immunogenicity of repeated doses of REGEN-COV 1,200 mg (n=729) compared to placebo (n=240), administered subcutaneously in healthy adults every 4 weeks for 24 weeks. During the 28-day assessment period, adverse events were reported in 52% (380) of REGEN-COV participants and 46% (111) of placebo participants. Injection site reactions occurred in 12% and 4% of participants following a single dose of REGEN-COV and placebo, respectively; and with repeat dosing injection site reactions occurred in 35% (252) of REGEN-COV participants and 16% (38) of placebo participants. Hypersensitivity reactions occurred in 1% (8) of REGEN-COV participants, all of which were mild to moderate.
About the REGEN-COV Antibody Cocktail
REGEN-COV (casirivimab and imdevimab) is a cocktail of two monoclonal antibodies that was designed specifically to block infectivity of SARS-CoV-2, the virus that causes COVID-19, using Regeneron's proprietary VelocImmune® and VelociSuite® technologies. The two potent, virus-neutralizing antibodies that form the cocktail bind non-competitively to the critical receptor binding domain of the virus's spike protein, which diminishes the ability of mutant viruses to escape treatment and protects against spike variants that have arisen in the human population, as detailed in Cell and Science.
REGEN-COV is currently available via emergency or temporary pandemic use authorizations in more than 20 countries, including in the U.S., European Union, India, Switzerland and Canada, and is also fully approved in Japan.
Information on how to access REGEN-COV throughout the U.S. is available from the Department of Health and Human Services and the National Infusion Center Association.
In the U.S., for post-exposure prophylaxis use REGEN-COV 1,200 mg (600 mg casirivimab and 600 mg imdevimab) can be administered by subcutaneous injection (4 injections), or by intravenous infusion (as short as 20 minutes). It is available as a co-formulated single vial, or in individual vials to be administered together. For people who aren't expected to mount an adequate immune response to vaccination and who have an ongoing exposure to SARS-CoV-2 for more than four weeks, the initial 1,200 mg dose can be followed by subsequent repeat dosing of REGEN-COV 600 mg once every four weeks, for the duration of ongoing exposure.
In addition to post-exposure prophylaxis, in November 2020 the FDA authorized REGEN-COV in the U.S. under an EUA to treat mild-to-moderate COVID-19 in adults and pediatric patients (12 years of age and older weighing ≥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.
About Regeneron's VelocImmune Technology
Regeneron's VelocImmune technology utilizes a proprietary genetically engineered mouse platform endowed with a genetically humanized immune system to produce optimized fully human antibodies. When Regeneron's President and Chief Scientific Officer George D. Yancopoulos was a graduate student with his mentor Frederick W. Alt in 1985, they were the first to envision making such a genetically humanized mouse, and Regeneron has spent decades inventing and developing VelocImmune and related VelociSuite technologies. Dr. Yancopoulos and his team have used VelocImmune technology to create approximately a quarter of all original, FDA-approved fully human monoclonal antibodies currently available. This includes REGEN-COV (casirivimab and imdevimab), Dupixent® (dupilumab), Libtayo® (cemiplimab-rwlc), Praluent® (alirocumab), Kevzara® (sarilumab), Evkeeza® (evinacumab-dgnb) and Inmazeb™ (atoltivimab, maftivimab and odesivimab-ebgn).
AUTHORIZED USES AND IMPORTANT SAFETY INFORMATION
Treatment:
REGEN-COV 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 progression to severe COVID-19, including hospitalization or death
Limitations of Authorized Use (Treatment)
• 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
• 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
Post-Exposure Prophylaxis:
REGEN-COV is authorized in adult and pediatric individuals (12 years of age and older weighing at least 40 kg) for post-exposure prophylaxis of COVID-19 in individuals who are at high risk for progression to severe COVID-19, including hospitalization or death, and are:
• not fully vaccinated or who are not expected to mount an adequate immune response to complete SARS-CoV-2 vaccination (for example, individuals with immunocompromising conditions including those taking immunosuppressive medications) and
⋅ have been exposed to an individual infected with SARS-CoV-2 consistent with close contact criteria per Centers for Disease Control and Prevention (CDC) or
⋅ who are at high risk of exposure to an individual infected with SARS-CoV-2 because of occurrence of COVID-19 infection in other individuals in the same institutional setting (for example, nursing homes, prisons)
Limitations of Authorized Use (Post-Exposure Prophylaxis)
• Post-exposure prophylaxis with REGEN-COV is not a substitute for vaccination against COVID-19
• REGEN-COV is not authorized for pre-exposure prophylaxis for prevention of COVID-19
REGEN-COV has not been approved, but has been authorized for emergency use by FDA
These uses are 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
Criteria for Identifying High Risk Individuals
Please refer to the Fact Sheet for Healthcare Providers for criteria for identifying high risk individuals
SARS-CoV-2 Viral Variants
Circulating SARS-CoV-2 viral variants may be associated with resistance to monoclonal antibodies. Healthcare providers should review the Antiviral Resistance information in Section 15 of the Fact Sheet for details regarding specific variants and resistance, and refer to the CDC website
(https://www.cdc.gov/coronavirus/2019-ncov/transmission/variant-cases.html) as well as information from state and local health authorities regarding reports of viral variants of importance in their region to guide treatment decisions.
Important Safety Information
REGEN-COV (casirivimab and 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
• Contraindication:
REGEN-COV is contraindicated in individuals with previous severe hypersensitivity reactions, including anaphylaxis, to REGEN-COV
• Warnings and Precautions:
⋅ Hypersensitivity Including Anaphylaxis and Infusion-Related Reactions: Serious hypersensitivity reactions, including anaphylaxis, have been observed with administration of REGEN-COV. If signs or symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue administration and initiate appropriate medications and/or supportive therapy. Hypersensitivity reactions occurring more than 24 hours after the infusion have also been reported with the use of REGEN-COV under EUA. 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: fever, difficulty breathing, reduced oxygen saturation, chills, nausea, arrhythmia (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, vasovagal reactions (e.g., pre-syncope, syncope), dizziness, fatigue and diaphoresis. Consider slowing or stopping the infusion and administer appropriate medications and/or supportive care if an infusion-related reaction occurs
⋅ 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, arrhythmia (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:
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 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:
⋅ COV-2067 (Treatment): 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. Three subjects receiving the 8,000 mg dose of REGEN-COV, and one subject receiving the 1,200 mg casirivimab and 1,200 mg imdevimab, had 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. 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
⋅ COV-2069 (Post-exposure prophylaxis): In subjects who were SARS-CoV-2 negative at baseline (Cohort A), injection site reactions (all grade 1 and 2) occurred in 55 subjects (4%) in the REGEN-COV group and 19 subjects (2%) in the placebo group. The most common signs and symptoms of injection site reactions which occurred in at least 1% of subjects in the REGEN-COV group were erythema and pruritus. Hypersensitivity reactions occurred in 2 subjects (0.2%) in the REGEN-COV group and all hypersensitivity reactions were grade 1 in severity. In subjects who were SARS-CoV-2 positive at baseline (Cohort B), injection site reactions, all of which were grade 1 or 2, occurred in 6 subjects (4%) in the REGEN-COV group and 1 subject (1%) in the placebo group. The most common signs and symptoms of injection site reactions which occurred in at least 1% of subjects in the REGEN-COV group were ecchymosis and erythema
⋅ COV-2093 (Subcutaneous Dosing): Injection site reactions occurred in 12% and 4% of subjects following single dose administration in the REGEN-COV and placebo groups, respectively. Remaining safety finding following subcutaneous administration in the REGEN-COV group were similar to the safety findings observed with intravenous administration in COV-2067. With repeat dosing, injection site reactions occurred in 252 subjects (35%) in the REGEN-COV group and 38 subjects (16%) in the placebo group; all injection site reactions were grade 1 or 2 in severity. Hypersensitivity reactions occurred in 8 subjects (1%) in the REGEN-COV group; and all hypersensitivity reactions were grade 1 or 2 in severity. There were no cases of anaphylaxis.
• Patient Monitoring Recommendations: Clinically monitor patients during infusion and observe patients for at least 1 hour after intravenous infusion or subcutaneous dosing is complete
• Use in Specific Populations:
⋅ Pregnancy: There are insufficient data to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. REGEN-COV should only be used during pregnancy if the potential benefit outweighs the potential risk for the mother and the fetus
⋅ Lactation: 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. 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
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