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INTRODUCTION

As of early October 2021, 44 million cases of coronavirus disease 2019 (COVID-19), including more than 700,000 deaths, have been reported in the United States. Over the past few months, the delta variant (B.1.617.2) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become the predominant strain in the United States, according to the U.S. Centers for Disease Control and Prevention (CDC), accounting for nearly 99% of currently circulating strains as of September 25, 2021. While other strains are considered variants of interest or variants being monitored (e.g., gamma variant), delta is the only variant of current concern in the United States. This strain has caused tremendous morbidity and mortality across the world and in this country, especially in the unvaccinated population, which accounts for about 90% of hospitalizations and deaths. Encouraging news as of early October 2021 is that more than 200,000,000 Americans 18 years or older are fully vaccinated (defined as receiving 2 mRNA vaccine doses or 1 adenovirus vaccine dose), which is approximately 78% of the U.S. population. In addition, moderately to severely immunocompromised patients who received either mRNA vaccine (Pfizer/BioNTech or Moderna) are eligible for a third dose of their vaccine product 28 or more days after the second dose. More than 6 million such people have received a third dose of their primary mRNA COVID-19 vaccine since the initial U.S. Food and Drug Administration (FDA) emergency authorization of this indication on August 13, 2021.

On September 30, 2021, FDA approved booster doses of the Pfizer/BioNTech vaccine for patients 18 years and older with certain qualifying health conditions, but this specific authorization applies only to patients who received a 2-dose series of that vaccine 28 or more days earlier. The Pfizer/BioNTech vaccine is now fully approved by FDA for the primary 2-dose series under the brand name Comirnaty.

Despite slow but steady progress in COVID-19 vaccinations, some people remain vaccine-hesitant, and many of them appear unlikely to be vaccinated. For those who become infected with SARS-CoV-2, treatment options are extremely important as SARS-COV-2 makes a likely transition from a pandemic to an endemic virus. Treatments that are available in the outpatient setting will be especially valuable so that infections can be arrested and cured before hospitalization is needed or death occurs. Significant progress has been made with monoclonal antibody therapies for COVID-19 that are now formally recommended in treatment guidelines.

In this continuing pharmacy education program, monoclonal antibody therapies are highlighted and their place in current therapy of SARS-CoV-2 infections and COVID-19 described in a question-and-answer format.

What is the availability of COVID-19 monoclonal antibodies in the United States, and to what degree are they being used?

As the role of monoclonal antibodies in COVID-19 treatment has evolved, demand has followed suit nationally, especially in those areas where vaccination rates remain subpar. With the delta variant sparking the latest rise in cases, the need for monoclonal antibodies has skyrocketed. In mid-July, Regeneron reported shipping less than 25,000 doses of the combination of casirivimab and imdevimab (REGEN-COV) per week, but shipments have increased up to 168,000 doses per week, with most orders sent to areas with low vaccination rates. When a direct ordering process to purchase monoclonal antibodies was available, approximately 70% of orders went to just 7 states: Alabama, Florida, Texas, Mississippi, Tennessee, Georgia, and Louisiana.

To keep up with demand, the U.S. government purchased an additional 1.4 million doses of REGEN-COV from Regeneron on September 14, 2021, bringing the total purchased amount to nearly 3 million doses. An additional 388,000 doses of etesevimab were also purchased by the U.S. government from Eli Lilly and Company to complement doses of bamlanivimab that were previously purchased. The cost of these monoclonal antibodies is significantly higher than COVID-19 vaccines.

To streamline the distribution process of monoclonal antibodies during this surge in demand, the U.S. Department of Health and Human Services (HHS) transitioned from a direct ordering process and enacted a state/territory-coordinated distribution system on September 13, 2021. With this system, HHS allocates the amount of monoclonal antibody products each state or territory receives on a weekly basis based on product use, availability, and COVID-19 case burden. State and territorial health departments subsequently determine where product is distributed throughout their jurisdiction. An interactive map displaying the distribution of monoclonal antibodies throughout the United States is available through the HHS. The data displayed are based on shipments reported by the distributor; however, this is not a guarantee of availability.

As of September 10, HHS had shipped 2.17 million doses of COVID-19 monoclonal antibodies, and nearly nearly 1 million of these doses had been used. As hospitals overflow with patients in holding areas and subsequent diversions common, creative measures have been used nationally to deploy mobile monoclonal antibody clinics. One example of this is in Johnson County in North Carolina, where mobile clinics have been activated with the goal of treating up to 100 patients daily to prevent hospitalizations and death. Patients seeking such treatments should coordinate with their health care provider before contacting a location.

What are potential advantages of monoclonal antibodies?

Assuming logistics are in place to administer monoclonal antibodies either subcutaneously or intravenously, these therapies have a number of advantages over other options in patients with SARS-CoV-2 infections. First, unlike convalescent plasma, monoclonal antibodies are designed to target specific viral epitopes and can be given in a numeric quantity, providing high titers of the neutralizing antibodies needed for SARS-CoV-2. This should allow these therapies to be effective against the virus, including variants that may arise. In addition, there is no reliance upon blood donors for these products, which can be mass produced to meet increased demands.¹  

Of course, oral therapies would be even more convenient, and a number of these are in development. Those will be detailed in future COVID-19 updates on the Power-Pak website.

How do monoclonal antibodies work?

The monoclonal antibodies currently authorized by FDA work through binding to the viral S protein (coronavirus spike protein), thus neutralizing the ability of SARS-CoV-2 to fuse with the target host cell. Casirivimab and imdevimab were chosen specifically from among thousands of initial antibodies due to their ability to bind to 2 separate but distinct sites on the receptor-binding domain. This feature makes it unlikely that a mutation will result in clinically significant resistance to both antibodies simultaneously.¹

Sotrovimab inhibits an undefined step after viral attachment but prior to viral fusion with cell membranes.

What key studies support use of the monoclonal antibodies currently authorized in the United States?

Bamlanivimab + Etesevimab

Postexposure Prophylaxis: In the phase 3 BLAZE-2 study, bamlanivimab (as monotherapy) was compared with placebo in 74 skilled-nursing and assisted-living facilities with at least 1 confirmed SARS-CoV-2 index case based on a primary endpoint of symptomatic COVID-19 within 8 weeks of randomization. Among 966 staff or residents who were confirmed negative for SARS-CoV-2 at baseline, those who received bamlanivimab had a statistically significant decrease in symptomatic COVID-19 (8.5% vs. 15.2%; adjusted OR 0.43 [95% CI 0.28–0.68]). No deaths occurred in the treatment group and 5 in the placebo arm were attributed to COVID-19. Treatment was well tolerated, with fewer than 4% of participants discontinuing therapy within prespecified evaluation timeframes.²

To date, no data exist for the currently authorized combination with etesevimab, but the FDA granted the emergency use authorization (EUA) for postexposure prophylaxis based on the totality of evidence.

Treatment: In the Phase 3 BLAZE-1 study, ambulatory participants with mild-to-moderate COVID-19 at high risk for progression to severe disease were randomly assigned to bamlanivimab/etesevimab given together or placebo. Participants were enrolled within 3 days of laboratory-confirmed SARS-CoV-2. The primary outcome — COVID-19–attributed hospitalization or death by day 29 — occurred in 2.1% of patients on active treatment versus 7.0% of those on placebo (absolute risk difference –4.8%; 95% CI, –7.4 to –2.3; P <0.001). Mortality occurred in 10 participants on placebo compared with none of those receiving bamlanivimab/etesevimab; 9 of the 10 deaths were attributed to COVID-19.³

The EUA for bamlanivimab monotherapy was revoked in April 2021 due to concerns over resistance, but it was reinstated for combination therapy of bamlanivimab and etesevimab administered together in states, territories, and U.S. jurisdictions where recent data show the combined frequency of variants resistant to both agents is less than 5%. In vitro assays suggest that when these agents are administered together, activity is retained against the delta variant, which is by far the most widely circulating variant currently in the United States. While resumption was granted for bamlanivimab/etesevimab, most institutions are still using casirivimab/imdevimab because of its known activity against the delta variant and the fact that the latest government process for allocation is based on the product ordered previously. In addition, bamlanivimab/etesevimab must be administered intravenously.

Casirivimab/Imdevimab

Postexposure Prophylaxis: Participants 12 years of age or older in the COVID-19 Phase 3 Prevention Trial were randomly assigned to subcutaneous casirivimab and imdevimab or placebo within 96 hours of a confirmed SARS-CoV-2–infected household contact. Patients were stratified by age and geography. The primary efficacy endpoint, development of symptomatic COVID-19 by day 28, was statistically decreased in the casirivimab/imdevimab group compared with placebo. Symptomatic SARS-CoV-2 infection occurred in 11 of 753 participants (1.5%) of the active treatment group compared with 59 of 752 participants (7.8%) in the placebo group, a statistically significant reduction (P <0.001). Of note, in patients who developed symptomatic COVID-19, treatment with casirivimab/imdevimab resulted in a median time of symptom resolution that was 2 weeks shorter compared with those receiving placebo. Participants tolerated the casirivimab and imdevimab well with no major dose-limiting side effects documented.⁴

Treatment: The most recent results for this combination monoclonal antibody treatment regimen come from a unique, adaptive trial. Regeneron was responsible for designing the study and gathering all data, and an independent data and safety monitoring committee was responsible for recommendations regarding ultimate trial modification and termination. Initially, participants within a phase 1/2 study were randomized to intravenous casirivimab/imdevimab 2400 mg or 8000 mg or to placebo. Based on results from these phases in November 2020, the trial was amended to ensure all participants had at least 1 risk factor for severe COVID-19, and doses of active agents were lowered to either 2400 mg or 1200 mg. Furthermore, in February 2021, the independent data and safety monitoring committee recommended dropping the placebo assignments, with later participants receiving only active agent.⁵

The phase 3 portion involved a number of different groups including a cohort ages 18 years or older, another cohort younger than 18 years, and a final cohort of participants who were pregnant at randomization. The primary endpoint consisted of the percentage of patients who experienced COVID-19 hospitalization or death from any cause through day 29. Secondary endpoints included this endpoint specifically for days 4 to 29 and time to resolution of COVID-19 symptoms.⁵

The primary endpoint in this study occurred in 18 of 1,355 participants (1.3%) in the casirivimab/imdevimab 2400 mg arm (1.3%) and 62 of 1,341 participants (4.6%) in the placebo group who had undergone randomization concurrently, a statistically significant difference favoring the treatment group. For the 1200 mg arm of the study, the primary outcome occurred in 7 of 736 participants (1.0%), compared with 24 of 748 participants (3.2%) receiving placebo, also a statistically significant advantage for the casirivimab/imdevimab group. Receipt of study drug resulted in a 4-day median reduction in time to symptom resolution (10 vs. 14 days; P <0.001). Study drug was well tolerated with infusion-related reactions (grade 2 or higher) occurring in fewer than 1% of participants. Casirivimab/imdevimab was efficacious across various subgroups, including those who were SARS-CoV-2 antibody positive at baseline. Specific details regarding the pregnant population were not detailed in this publication.⁵

While these studies were completed mostly during times when the delta variant was not prevalent, the combination of casirivimab/imdevimab has demonstrated in vitro activity versus this currently dominant strain.

Sotrovimab

Treatment: Sotrovimab was originally developed using an antibody isolated from a survivor of the 2003 SARS-CoV outbreak. It targets a preserved epitope between SARS-CoV and SARS-CoV-2 in the receptor-binding domain of the spike protein. While the peer-reviewed publication detailing clinical results is not yet available, sotrovimab in an interim analysis demonstrated efficacy in the treatment of outpatients with confirmed SARS-CoV-2. The data come from an interim analysis of the COMET-ICE trial, which demonstrated that outpatients with mild-to-moderate COVID-19 who were 55 years or older with at least 1 comorbidity benefited from intravenous sotrovimab over placebo for the primary endpoint of hospitalization for more than 24 hours or death. The comorbidities required for inclusion were diabetes, obesity, chronic kidney disease, heart failure, moderate-to-severe asthma, or chronic obstructive pulmonary disorder. The primary endpoint occurred in 1% of participants receiving sotrovimab and 7% of those on placebo (hazard ratio, 0.14 [95% confidence interval, 0.04–0.56]).

What are the current FDA authorizations for COVID-19 antibodies?

All three antibody treatments are authorized for treatment of mild-to-moderate COVID-19 in adults and pediatric patients 12 years or older weighing 40 kg or more with confirmed SARS-CoV-2 via direct testing and who are at high risk for progression to severe COVID-19, including hospitalization and death. Bamlanivimab/etesevimab as well as casirivimab/imdevimab are also authorized for postexposure prophylaxis in the same age groups in patients who are at high risk of progression to severe COVID-19, not fully vaccinated, or not expected to mount an adequate immune response. Because of the broad nature of these recommendations, many patients are expected to fulfill criteria for administration of monoclonal antibodies.

What are the recommendations for monoclonal antibodies in the COVID-19 guidelines of the National Institutes of Health?

Treatment

Any of the three antibody options (bamlanivimab/etesevimab, casirivimab/imdevimab, or sotrovimab) may be used to treat patients with mild-to-moderate COVID-19 who are at high risk of clinical progression. For casirivimab/imdevimab, the intravenous infusion is preferred, but if that route is not practical or would cause a delay in treatment, subcutaneous administration may be used. The National Institutes of Health (NIH) guidelines specify that the strength of evidence for various conditions varies depending on the specifics of the clinical studies. A list of conditions/factors that were well represented and those with limited representation but considered appropriate for treatment with monoclonal antibodies is included in Table 1.⁶

Postexposure Prophylaxis

The NIH panel recommends either casirivimab plus imdevimab OR bamlanivimab plus etesevimab for SARS-CoV-2–exposed patients at high risk for progression to severe COVID-19 disease should they become infected. This includes fully vaccinated individuals who are not expected to mount an adequate immune response due to immunocompromising condition or medication and individuals who not are fully vaccinated. Bamlanivimab/etesevimab is given intravenously, and casirivimab/imdevimab can be administered intravenously or subcutaneously.⁶

A summary table with pertinent characteristics of these monoclonal antibodies with some additional information can be found in Table 2.

When will testing capacity be adequate in the United States?

A major impediment in the United States overall COVID-19 plan has been the lack of readily available, affordable testing modalities. As of early October, the White House has announced that an additional $1 billion will be spent on rapid at-home COVID tests. While many of these are antigen tests that are not as sensitive as those offered by standard laboratories often used by state agencies, identification of SARS-CoV-2 would allow more efficient quarantine to limit spread and the ability to initiate potentially life-saving therapies, such as monoclonal antibodies, much more quickly. This would be especially timely and important for this coming winter as there are predictions from CDC director Dr. Rochelle Walensky that we could see a significant number of influenza cases during the 2021–22 year. It is pretty easy to see that this coming winter will be a busy season for pharmacists across the United States. 

REFERENCES

1. Taylor PC, Adams AC, Hufford MM, et al. Neutralizing monoclonal antibodies for treatment of COVID-19. Nat Rev Immunol. 2021;21:382–393.
2. Cohen MS, Nirula A, Mulligan MJ, et al. Effect of bamlanivimab vs placebo on incidence of COVID-19 among residents and staff of skilled nursing and assisted living facilities. JAMA. 2021;326:46–55.
3. Dougan M, Nirula A, Azizad M, et al. Bamlanivimab plus etesevimab in mild or moderate COVID-19. N Engl J Med. 2021;385:1382–1392.
4. O’Brien MP, Forleo-Neto E, Musser BJ, et al. Subcutaneous REGEN-COV antibody combination to prevent COVID-19. N Engl J Med. 2021;385:1184–1195.
5. Weinreich DM, Sivapalasingam S, Norton T, et al. REGEN-COV antibody combination and outcomes in outpatients with COVID-19. N Engl J Med. 2021. doi: 10.1056/NEJMoa2108163. Published online September 29, 2021.
6. COVID-19 Treatment Guidelines Panel. Coronavirus disease 2019 (COVID-19) treatment guidelines. National Institutes of Health. October 7, 2021. https://www.covid19treatmentguidelines.nih.gov/

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