U.S. FDA Authorizes Regeneron’s REGN-COV2 Monoclonal Antibody for Emergency Use Authorization Targeting Select COVID-19 Patients

U.S. FDA Authorizes Regeneron’s REGN-COV2 Monoclonal Antibody for Emergency Use Authorization Targeting Select COVID-19 Patients TrialsiteN

The monoclonal antibody cocktail developed by Regeneron and made well-known by POTUS during his stay at Walter Reed Medical Center has received Emergency Use Authorization (EUA) from the U.S. Food and Drug Administration (FDA). Initially called REGN-COV-2 and also known as Casirivimab and imdevimab, when administered together the two experimental monoclonal antibodies are authorized for the treatment of mild to moderate COVID-19 in adults, as well as in pediatric patients at least 12 years of age and weighing at least 40 kg, who have received positive results of direct SARS-CoV-2 viral testing and are at high risk for progressing to severe COVID-19 and/or hospitalization. This is the second monoclonal antibody to be authorized for emergency use by the FDA followed by Eli Lilly’s experimental product originally called LY-COV555. It’s the first monoclonal antibody cocktail to be approved by the FDA for EUA targeting COVID-19.  Regeneron’s press release declared that the clinical evidence derived from outpatient trials indicate that monoclonal antibodies such as REGN-COV-2 have the greatest benefit when given early after diagnosis and in patients who have not yet mounted their own immune response or who have high viral load. Initial doses of REGN-COV2 will be made available to approximately 300,000 patients, with no medication out-of-pocket costs, under the U.S. government allocation program. However, the cost incurred by the provider as measured by the effort and infrastructure of the provider to administer the novel monoclonal antibody cocktail may be charged to the patient. Again, this EUA applies to recently diagnosed, mild to moderate COVID-19 in high-risk patients. TrialSite notes this authorization doesn’t help the current problem of no approved or EUA treatment for mild to moderate COVID-19 cases on an ambulatory or outpatient basis with no initial high risk factors. 

A Fact Sheet for Health Care Providers outlines the criteria for the definition of ‘high-risk’ patients involving the use of Casirivimab and imdevimab. This monoclonal antibody is not authorized for use in patients who are hospitalized or require oxygen therapy due to COVID-19, 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. Interestingly, POTUS was administered the drug while hospitalized in the hospital but could have been deemed high risk under compassionate use.

TrialSite Breakdown this update below.

How much data did the FDA have to work with in making this decision?

According to the recent press release Regeneron’s President and Chief Scientific Officer George D. Yancopoulos, MD, PhD, declared “REGN-COV2 is designed to mimic what a well-functioning immune system does by using very potent antibodies to neutralize this virus.” He continued “Data from approximately 800 non-hospitalized patients showed significant reductions in virus levels within days of receiving REGN-COV2, which were associated with significantly fewer medical visits.” Note that over 7,000 patients are involved with clinical trials involving REGN-COV2 to date. 

Which patients benefited most?

President Yancopoulos also shared that “…[T]his benefit was greatest in patients most at risk for poor outcomes due to high viral load, ineffective immune response at baseline or pre-existing risk factors.”

How many doses will be available as part of the initial batch?

Regeneron now expects to have REGEN-COV2 treatment doses ready for approximately 80,000 patients by the end of November, approximately 200,000 patients by the first week of January, and approximately 300,000 patients in total by the end of January 2021.

Why not more doses?

Production of monoclonal antibodies is a complex, time- and labor-intensive process that requires deep expertise. Utilizing production and manufacturing platforms developed over decades, Regeneron rapidly scaled up REGEN-COV2, beginning in the early days of the pandemic with support from the Biomedical Advanced Research and Development Authority (BARDA), part of the Office of the Assistant Secretary for Preparedness and Response at the U.S. Department of Health and Human Services. 

What about in 2021?

Regeneron plans on boosting production to grow global supply in partnership with Roche who will scale up that production capability worldwide.

When does Regeneron start shipping?

Immediately

Who is the distributor?

Amerisource Bergen, a national distributor, which will distribute the therapy as directed by the government.

Did Regeneron receive federal government (taxpayer) money as part of Operation Warp Speed?

Yes. In July, the company announced an injection of $450 million from the federal government as part of an initial supply agreement of REGN-COV2. 

Is the initial 300,000 dose batch free for the patient?

Well, the out-of-pocket drug cost is but most certainly there will be costs for administration services at the hospital or health center. The company agrees to provide 300,000 doses at no cost to patients, however, as mentioned previously, healthcare facilities can charge significant fees related to the administration of this complex drug.

How will the doses be allocated?

The U.S. government will coordinate with state authorities to allocate REGN-COV2 on a weekly basis based on the number of COVID-19 cases in each state. Again the initial 300,000 won’t be charged to the patient but has been mentioned health systems and hospitals will most certainly charge for the administration of the experimental drug. 

What is the recommendation dosage under the EUA?

Under the EUA, the recommended dose is 1,200 mg of casirivimab and 1,200 mg of imdevimab (2,400 mg total) administered as a single intravenous infusion. The authorization is based on positive Phase 2 data announced in September and October from the first 799 adults in an ongoing randomized, double-blind, placebo-controlled trial of non-hospitalized patients (“outpatients”) with COVID-19.

Does an FDA EUA mean that the drug works?

No. The FDA grants Emergency Use Authorization to medicines that may help diagnose, treat or prevent a life-threatening disease when adequate and approved alternatives are not available. The EUA is temporary and does not take the place of a formal biologics license application (BLA) submission review and approval process. This use is authorized only for the duration of the declaration that circumstances exist justifying the authorization of the emergency use, unless terminated or revoked sooner. Casirivimab and imdevimab have not been approved by FDA and remain investigational. Evaluation of its safety and efficacy is ongoing in multiple clinical trials. Data from these trials will be used to support a future BLA submission. 

How do healthcare providers get more information?

Health care providers should review the Fact Sheet for detailed information on the authorized use and requirements of the EUA and may call 844-734-6643 for more information. Please see the Fact Sheet and FDA Letter of Authorization here.

Does REGN-COV2 continue to be evaluated in clinical trials?

Yes. REGEN-COV2 continues to be evaluated in Phase 2/3 clinical trials for the treatment of COVID-19 in certain hospitalized and non-hospitalized patients, the Phase 3 open-label RECOVERY trial of hospitalized patients in the UK, and a Phase 3 trial for the prevention of COVID-19 in household contacts of infected individuals. To date, more than 7,000 people have participated in REGEN-COV2 clinical trials.

What is REGN-COV2?

REGN-COV2 is a cocktail of two monoclonal antibodies (casirivimab and imdevimab, also known as REGN10933 and REGN10987, respectively) and was designed specifically to block infectivity of SARS-CoV-2, the virus that causes COVID-19.

To develop REGEN-COV2, Regeneron scientists evaluated thousands of fully-human antibodies produced by the company’s VelocImmune® mice, which have been genetically modified to have a human immune system, as well as antibodies identified from humans who have recovered from COVID-19. The two potent, virus-neutralizing antibodies that form REGEN-COV2 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 Science.

REGEN-COV2’s development and manufacturing has been funded in part with federal funds from BARDA under OT number: HHSO100201700020C. Regeneron continues to increase in-house production of REGEN-COV2, and the company has partnered with Roche to increase the global supply of REGEN-COV2 beginning in 2021. If REGEN-COV2 proves safe and effective in clinical trials and regulatory approvals are granted, Regeneron will manufacture and distribute it in the U.S. and Roche will develop, manufacture and distribute it outside the U.S. Once both companies are at full manufacturing capacity in 2021, there are expected to be at least 2 million treatment doses available annually.

Did the initial study get off to an unorthodox start?

Yes. TrialSite was the only media that reported on the unorthodox nature of how these clinical trials started. Initially there was no traditional Phase 1 clinical trial but rather a group of hospitalized patients with COVID-19 that were part of a sentinel population cohort accepted by the U.S. FDA. During the administering of this highly novel monoclonal antibody cocktail, the Drug Monitoring Safety Board had access to blinded information that apparently the investigational biological cocktail was  working. Hence they allowed for the study to proceed even before Regeneron could view that blinded data according to a Regeneron spokesperson answering questions from TrialSite News

The company disclosed clinical trials including Phase 3 “contacts” study even before a formal Phase 1 was concluded.  More than likely due to the pandemic conditions, the whole affair was not typical.

Was Regeneron open and accessible for questioning by TrialSite?

Yes. They were very friendly and open to answering questions.

What authority governs the EUA?

Casirivimab and imdevimab injection (REGEN-COV2) is an investigational combination therapy and has been authorized by FDA for the emergency use described above. Casirivimab and imdevimab injection is not FDA approved for any use. Safety and effectiveness of casirivimab and imdevimab injection have not yet been established for the treatment of COVID-19.

This authorized use is 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

What are limitations associated with use?

Casirivimab and imdevimab injection 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 casirivimab and imdevimab injection has not been observed in patients hospitalized due to COVID-19. Monoclonal antibodies, such as casirivimab and imdevimab, may be associated with worse clinical outcomes when administered to hospitalized patients requiring high flow oxygen or mechanical ventilation with COVID-19.

What are monitoring recommendations?

Clinically monitor patients during infusion and observe patients for at least 1 hour after infusion is complete

How does Regeneron define 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, OR
  • sickle cell disease, OR
  • congenital or acquired heart disease, OR
  • neurodevelopmental disorders, for example, 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

What are warnings and precautions associated with this experimental treatment?

  • Hypersensitivity Including Anaphylaxis and Infusion-Related Reactions: There is a potential for serious hypersensitivity reaction, including anaphylaxis, with administration of casirivimab and imdevimab injection. If signs or symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue administration and initiate appropriate medications and/or supportive therapy. Infusion-related reactions have been observed with administration of casirivimab and imdevimab injection. Signs and symptoms of infusion related reactions may include fever, chills, nausea, headache, bronchospasm, hypotension, angioedema, throat irritation, rash including urticaria, pruritus, myalgia, and/or dizziness. If an infusion-related reaction occurs, consider slowing or stopping the infusion and administer appropriate medications and/or supportive care.
  • Limitations of Benefit and Potential for Risk in Patients with Severe COVID-19: Benefit of treatment with casirivimab and imdevimab injection has not been observed in patients hospitalized due to COVID-19. Monoclonal antibodies, such as casirivimab and imdevimab, may be associated with worse clinical outcomes when administered to hospitalized patients requiring high flow oxygen or mechanical ventilation with COVID-19. Therefore, casirivimab and imdevimab injection is not authorized for use in 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.

What are some reported adverse reactions?

  • Serious adverse events (SAEs) were reported in 4 (1.6%) patients in the casirivimab and imdevimab injection 2,400 mg group, 2 (0.8%) patients in casirivimab and imdevimab injection 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 casirivimab and imdevimab injection), intestinal obstruction and dyspnea (8,000 mg casirivimab and imdevimab injection) and COVID-19, pneumonia and hypoxia (placebo). Casirivimab and imdevimab injection are not authorized at the 8,000 mg dose (4,000 mg casirivimab and 4,000 mg imdevimab).

What is known about use in pregnant women or nursing mothers?

Currentl,y there is no clinical experience in the use of casirivimab and imdevimab injection in COVID-19 patients who are pregnant or nursing mothers. In the case of pregnancy, the REGN-COV2 combination therapy should be used during pregnancy only if the potential benefit justifies the potential risk for the mother and the fetus.

As far as nursing mothers, the development and health benefits of breastfeeding should be considered along with the mother’s clinical need for REGN-COV2 injection and any potential adverse effects on the breastfed child from the injection of the experimental monoclonal antibody cocktail or from the underlying maternal condition.

Regeneron Background

Regeneron (NASDAQ: REGN) is a leading biotechnology company that invents life-transforming medicines for people with serious diseases. Founded and led for over 30 years by physician-scientists, our unique ability to repeatedly and consistently translate science into medicine has led to eight FDA-approved treatments and numerous product candidates in development, all of which were homegrown in our laboratories. Our medicines and pipeline are designed to help patients with eye diseases, allergic and inflammatory diseases, cancer, cardiovascular and metabolic diseases, pain, infectious diseases and rare diseases.

Regeneron is accelerating and improving the traditional drug development process through our proprietary VelociSuite® technologies, such as VelocImmune, which uses unique genetically-humanized mice to produce optimized fully-human antibodies and bispecific antibodies, and through ambitious research initiatives such as the Regeneron Genetics Center, which is conducting one of the largest genetics sequencing efforts in the world

Does Regeneron’s press release contain a number of forward-looking statements that involve risks and uncertainties relating to future events and the future performance of the company?

Yes. See the press release for a comprehensive disclosure.