Helping the several million immuno­compromised Americans who are still “Prisoners of the Pandemic”

The rapid development of new weapons to fight the COVID-19 pandemic is a testament to the power of science, as well as to the commitment of the biopharmaceutical community and our academic and government partners. Physicians and patients now have important new tools including diagnostics, vaccines and monoclonal antibodies. In addition, oral antivirals will be added to the mix shortly. It is therefore tragic that several of these weapons – particularly monoclonal antibodies – are not being utilized optimally. A recent CNN article¹ by Elizabeth Cohen on monoclonal antibodies titled “Doctors are often unaware of the only treatment for early COVID-19” quotes Dr. Anthony Fauci, the President’s senior medical advisor. He describes use of monoclonal antibodies to treat early infection as “a very effective intervention for COVID-19.  It is underutilized, and we recommend strongly that we utilize this to its fullest … I've been trying to get attention paid to how easy it should be to get this done, but I understand that a lot of doctors don't fully appreciate that." The article also quotes Dr. Peter Chin-Hong, an infectious disease expert and professor at the UCSF School of Medicine, who says, "It's unconscionable ... We have an evidence-based drug, and it's provided free by the government, but there are barriers built into the system to get it."

Our failure to fully utilize the power of monoclonal antibodies has many unfortunate consequences – perhaps the most tragic relates to our failure to help the most vulnerable among us – i.e., the immunocompromised. The Centers for Disease Control and Prevention (CDC) estimates that 3% of U.S. adults are moderately to severely immunocompromised,² which equates to several million Americans. These individuals are either on immunosuppressive medicines (i.e., for organ transplants, or certain autoimmune diseases such as multiple sclerosis) or have conditions (i.e., certain cancers such as lymphoma or myeloma, or primary immunodeficiencies) that impair their immune response to vaccination. At Regeneron, we appreciate that universal vaccination is the best way to broadly protect the population from COVID-19; and we also believe that other options are required for the immunocompromised, who remain “prisoners of the pandemic” because many of them respond sub-optimally or not at all to vaccination. In the interests of scientific exchange, I outline in this document Regeneron’s thinking with regard to the science that supports the use of monoclonal antibodies to prevent SARS-CoV-2 infection in immunocompromised people.

In response to the COVID-19 pandemic, the U.S. Food and Drug Administration (FDA) has authorized a number of medicines under Emergency Use Authorization (EUA). Thus, while monoclonal antibodies targeting SARS-CoV-2 have not yet been approved in the U.S., they are currently authorized by the FDA for use in certain people who are at high risk of serious consequences from COVID-19:

• Treatment of non-hospitalized infected patients.^3-5
• Post-exposure prophylaxis for uninfected individuals who have been exposed to an infected person or are at high risk of such an exposure (e.g., if they are living in a nursing home or prison setting during an outbreak).^3-4

In the U.S., monoclonal antibodies are not currently authorized as a substitute for vaccination against COVID-19, or for pre-exposure prophylaxis for prevention of COVID-19, or for use in patients who are hospitalized due to COVID-19 or require oxygen therapy, or for people currently using chronic oxygen therapy because of an underlying comorbidity who require an increase in baseline oxygen flow rate due to COVID-19.

A recent study from Johns Hopkins University found that, despite vaccination, certain immunocompromised individuals were far more likely to have a breakthrough infection leading to hospitalization or death than other vaccinated individuals.⁶ Since many immunocompromised people cannot efficiently make their own antibodies, it would make sense to compensate for this immunodeficiency by proactively providing these individuals with monoclonal antibodies produced in the laboratory. Although monoclonal antibodies are authorized by the U.S. FDA to treat early COVID-19 in certain patients, they are not yet authorized for chronic protection of the immunocompromised.^3-5 Several experts have advocated for increased use in this setting:

• The Director of the FDA’s Center for Biologics Evaluation and Research (CBER), Dr. Peter Marks, who is widely considered as the nation’s leading expert on vaccine regulation, in October shared these personal views during a COVID-19 clinician call:⁷ “From the standpoint of having been a leukemia doctor, there are things we can do that are really simple though. If you have an individual who has received an anti-CD20 monoclonal antibody for either a hematologic malignancy or for an autoimmune disease in the past 6-12 months, it is unlikely that they are going to respond to vaccination and you probably want to consider pursuing prophylactic strategies such as using a monoclonal.” Patients who take anti-CD20 monoclonal antibodies are immunocompromised because these medicines impact the part of their immune system that makes antibodies.
• In a touching autobiographical essay,⁸ “There might finally be a COVID solution for immunocompromised people like me,” Dr. Lindsay Ryan, an immunocompromised physician working in the emergency room of a busy hospital, outlines how she was able to receive monoclonal antibodies in the preventative setting based on her ongoing workplace exposure. She notes that monoclonal antibodies are available for chronic prevention only for a “privileged” few due to “logistics and lack of awareness among both doctors and patients,” and she advocates for broader access for the immunocompromised.
• The former FDA commissioner Scott Gottlieb, in his appearance on Face the Nation on October 24,⁹ noted that he fully understands the struggles of the immunocompromised, having been an adult cancer chemotherapy patient himself. He states “Look, I don't think anyone should die from COVID now … There's two pockets of vulnerability: young children, who we will eventually be able to vaccinate; and then people who are immune-incompetent. They can't mount an effective response to the vaccines ... We have the tools to protect them. We could be using the antibody drugs on a prophylactic basis, giving them regular infusions, probably monthly infusions, to protect them ... There is an emergency use authorization sitting with the FDA right now for that specific use.”

The pleas of these public health experts are a response to the increasing evidence that the immunocompromised are particularly susceptible. Unfortunately, widespread vaccination of the general population will not protect the immunocompromised, many of whom will not make their own antibodies in response to vaccination.^10-15 Because significant numbers of asymptomatic or symptomatic breakthrough infections still occur among the vaccinated, even with a high level of vaccination, the SARS-CoV-2 virus will likely continue to circulate. Thus, if immunocompromised individuals try to resume their normal lives, they will encounter infected individuals and be at high risk of developing serious disease. If we fail to protect them, the immunocompromised will remain tragic “prisoners of the pandemic."

At Regeneron, we agree with outside experts that there is compelling rationale and real-world clinical trial data supporting the use of monoclonal antibodies to provide chronic (ongoing) protection for immunocompromised individuals who do not respond adequately to vaccines. Some of the data is summarized as follows:

• Many of the immunocompromised do not respond to vaccination, with approximately 40-60% having no antibodies generated by the vaccines after their second dose. In addition, between 50-100% of immunocompromised people who didn’t respond to their second dose remained seronegative after a third dose (based on research in people with certain blood cancers,¹⁰ solid organ transplants^11-14 and hemodialysis¹⁵).
• Clinical trials of monoclonal antibodies have shown that infected patients who lack their own antibodies – an important characteristic shared by the immunocompromised – had higher viral loads, took longer to resolve their symptoms and had worse clinical outcomes.^16-18 Administering monoclonal antibodies to such patients helped to rapidly decrease viral levels (>95% within 2 days¹⁷), significantly shortened symptom duration and reduced the risk of progressing to more severe disease – i.e., hospitalization and death – by approximately 70%¹⁶.
• Clinical trials have shown that prophylactic dosing with monoclonal antibodies can prevent symptomatic COVID-19 disease in uninfected individuals even if they live in the same household as an infected person.¹⁹ In a one-month prevention trial, the risk of symptomatic disease was reduced by 72% in the first week after receiving prophylactic antibody treatment (i.e., pre- and post-exposure prophylaxis), and 93% in the subsequent 2-4 weeks (pre-exposure prophylaxis).¹⁹ Recently, Regeneron announced additional, long-term findings from this same prevention trial, showing that a single dose of monoclonal antibodies prevented more than 80% of COVID-19 cases for the eight-month assessment period.²⁰
• In publications describing individual cases,^21-23 as well as in four case series,^24-27 treatment of immunocompromised individuals with monoclonal antibodies led to rapid viral clearance as well as rapid clinical improvement in the majority.

Monoclonal antibodies are currently authorized^3-5 to treat individuals, including the immunocompromised, who are already infected, or have been exposed to an infected individual or are at high risk of such an exposure. Prevailing clinical trial evidence^16-19 indicates that the earlier antibodies are administered during disease progression, the better the outcomes, with prevention before infection being the most powerful. In an increasingly vaccinated world, the immunocompromised will remain the most vulnerable without additional protection, such as what monoclonal antibodies might be able to provide.

The holidays are coming, when many of us will gather with friends and family, confident that the vaccines we received will protect us from the worst effects of this virus. We are anxious to help provide a similar confidence to the “prisoners of this pandemic,” so they too can enjoy the happiness and normalcy that comes with gathering with others, by providing chronic protection via regular monoclonal antibody treatments. We will work closely with the FDA towards this goal.  

The development and manufacturing of REGEN-COV have been funded in part with federal funds from the Biomedical Advanced Research and Development Authority, part of the U.S. Department of Health and Human Services’ Office of the Assistant Secretary for Preparedness and Response, under OT number: HHSO100201700020C.

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 treatment of mild to moderate COVID-19 in geographic regions where infection is likely to have been caused by a non-susceptible SARS-CoV-2 variant based on available information such as variant susceptibility to this drug and regional variant frequency.
    • FDA’s determination and any updates will be available at: https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization#coviddrugs.
  • 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 SARS-CoV-2 infection in other individuals in the same institutional setting (for example, nursing homes, prisons).

• Limitations of Authorized Use (Post-Exposure Prophylaxis)
  • REGEN-COV is not authorized for post-exposure prophylaxis of COVID-19 in geographic regions where exposure is likely to have been to a non-susceptible SARS-CoV-2 variant, based on available information including variant susceptibility to this drug and regional variant frequency.
    • FDA’s determination and any updates will be available at: https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization#coviddrugs.
  • 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 the 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 uses 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.

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 dose administration 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

Reporting Adverse Events

• 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 submitting 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 (medical.information​@regeneron.com)