In this article an infectious diseases pharmacist discusses some ABCs of SARS-CoV-2 monoclonal antibodies and how the ever-changing landscape of prevalent variants feels like a game of musical chairs.
Authored by: Timothy P. Gauthier, Pharm.D., BCPS, BCIDP
Information on this topic is rapidly changing, which may render content on this page inaccurate or incomplete. Readers are warned to reference primary information sources for answering questions for clinical care. Proceed with caution.
Article Posted: 17 March 2022
There are currently six SARS-CoV-2 monoclonal antibodies that have had an FDA Emergency Use Authorization (EUA). They are bamlanivimab from Eli Lilly, bamlanivimab/etesevimab from Eli Lilly, bebtelovimab from Eli Lilly, sotrovimab (Xevudy) from GlaxoSmithKline, casirivimab/imdevimab (REGEN-COV) from Regeneron, and tixagevimab/cilgevimab (Evusheld) from AstraZeneca. The EUAs for casirivimab/imdevimab and bamlanivimab/etesevimab do not currently allow for use in any US territory. Tixagevimab/cilgevimab is for pre-exposure prophylaxis only. Sotrovimab can be used for treatment but has lesser activity against Omicron BA.2. Bebtelovimab can be used for treatment but has limited clinical data to support use.
Monoclonal antibodies offer passive immunity against SARS-CoV-2. Their mechanism is different than antiviral drugs such as molnupiravir (Lagevrio), nirmatrelvir/ritonavir (Paxlovid), and remdesivir (Veklury). As the monoclonals fall in and out of favor during what feels like an endless game of music chairs, there are numerous points of differentiation and consideration that can be observed. These are relevant now and likely to be relevant in the future. Thus, this article is developed to identify and discuss the topic, but inspired by a recent article about Sesame Street and infectious diseases, this will be presented in the form of the ABCs.
As you go through this article, if there are any resources you are looking for, one of my favorite one-stop-shops is the HHS/ASP COVID Therapeutics webpage, at which you can click on the tile for the therapy of interest and many helpful links are there in one place.
A is for Age
Age is the strongest risk factor for poor outcomes with COVID-19 and has been used as one of the key elements in prioritization initiatives during times of monoclonal antibody scarcity. View the CDC webpage about people with certain conditions putting them at higher risk here.
Age is also a cut point for some of the EUAs. For example the sotrovimab limits use to patients 12 years and older.
B is for Body Weight
Like age, large body weights (e.g., BMI > 30 for obesity) are associated with poor COVID-19 outcomes. However, body weight is also one of the requirements found in monoclonal antibody EUAs, which limit use in pediatric patients to those that are 40 kg or more. Check each monoclonal’s Healthcare Professional (HCP) Fact Sheet for specific details within each EUA.
C is for COVID-19
The NIH COVID-19 Guidelines provide details on the clinical spectrum of diseases that SARS-CoV-2 can cause. Of importance, monoclonal antibodies have sometimes been associated with worse outcomes when given for severe or critical COVID-19. On the other hand, treatment of patients who are asymptomatic may not be appropriate. Each monoclonal must be considered in the context of which clinical presentations it is approved for.
D is for Direct SARS-CoV-2 Testing
When used for treatment, the EUAs have required a positive direct test for SARS-CoV-2, which could be either a PCR or antigen test.
Tixagevimab/cilgavimab on the other hand does not require a direct test, as it is currently only authorized for pre-exposure prophylaxis. Mind you testing can still be considered prior to treatment if concern for infection is present.
E is for Exposure
As patients sick with COVID-19 present for monoclonal evaluation, they may inadvertently expose other individuals to the virus. Infection control in the context of treatment or post-exposure prophylaxis of COVID-19 merits consideration. For example, you would not want an infusion center where high-risk cancer patients receive their treatment to co-mingle with patients sick with COVID-19.
Also on the topic of exposure, none of the monoclonals with an active EUA is approved for post-exposure prophylaxis, but should that become an option again (as it has been with casirivimab/imdevimab for example), classification of the exposure will be necessary. CDC definitions of exposure will be essential resources for this.
F is for Fact Sheet
As part of the EUA, the patient or care giver must be provided with the relevant fact sheet, which by-the-way can be hard to come by in other languages besides English or Spanish. Some patients may decline treatment after reviewing this fact sheet. It is important patients and caregivers be provided with this information so they can make an informed decision.
Additionally, the HCP Fact Sheet is a critical resource. It is similar to a package insert and the HCP Fact Sheets are updated rather frequently. It has been challenging to have HCP Fact Sheet content updated without any advanced notice, leaving healthcare facilities scrambling to make systems changes. One example of this is with the dose increase of tixagevimab/cilgavimab from 150mg/150mg to 300mg/300mg. That seemed to come totally out of the blue for many (if not all of us).
G is for Greatest Risk
Patients have to be at risk for progression to severe COVID-19 or other bad outcomes to be considered for treatment with the SARS-CoV-2 monoclonals. As the FDA EUAs have become more liberal in what constitutes “at risk”, those at greatest risk should be considered for prioritization.
H is for Hospitalization
In the United States none of the monoclonals have been authorized for use in treatment of patients hospitalized for COVID-19. They have been allowed in patients who are hospitalized for other reasons, but happen to acquire COVID-19 (as long as other inclusion/exclusion criteria are met). In the United Kingdom, casirivimab/imdevimab was authorized for use in patients hospitalized for COVID-19.
The concern with use in patients hospitalized for COVID-19 is that use has been associated with clinical worsening. There are data showing favorable results in seronegative hospitalized patients treated with casirivmab/imdevimab – but this is a topic for a future blog post!
I is for Indication
The indications can include pre-exposure prophylaxis, treatment, or post-exposure prophylaxis. As each monoclonal is considered, the current authorized indication must be observed. Take note that an agent may have numerous indications.
J is for Joint Safety Reported
Medication errors and serious adverse reactions should be jointly reported to FDA Medwatch as well as the product’s manufacturer. For example the sotrovimab HCP Fact Sheet notes these events must be reported within 7 calendar days of the healthcare provider’s awareness of it, using FDA Form 3500. It also notes the prescribing healthcare provider and/or the provider’s designee is/are responsible for mandatory responses to requests from the FDA for information about adverse events and medication errors.
Serious adverse events can include: death, a life-threatening adverse event, inpatient hospitalization, prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, a congenital anomaly/ birth defect, or other important medical event which may require medical or surgical intervention to prevent death, a life-threatening event, hospitalization, disability, or congenital anomaly.
K is for Kinetics
The half-life of the monoclonals can vary considerably, which means the duration of their protection may not be the same as repeat dosing is considered. The tixagevimab/cilgavimab HCP Fact Sheet initially said we could re-dose every 6 months for patients that continued to be at-risk and needed protection. Now that document says: “The SARS-CoV-2 variants that will be circulating in the United States when Evusheld may need to be redosed are not known at this time and therefore repeat dosing recommendations cannot be made; the Fact Sheets will be revised with repeat dosing recommendations in the future when more data are available.”
L is for Long Observation Period
All of the monoclonals currently require an observation period of one hour. That may not seem like a big deal, but when you consider it in the context of the volume of patients that may be seeking the therapy and note how long the visit takes with other intake/discharge activities, this is not a rapid process.
The 60 minute post-dose observation is in place due to the risk for infusion/injection-related reactions that may occur, including anaphylaxis.
M is for Mutations
As mutations have arisen and different variants have become predominant, we have played musical chairs with which monoclonals can be options. The HCP Fact Sheets now list the activity of each monoclonal against the variants. Here is a table I made using all the HCP Fact Sheet data:
You can use CDC resources to track variant predominance and CDC NOWCAST is pretty helpful too. Some states and counties also report variant predominance data.
N is for Neonatal Risks
Pregnancy and breastfeeding should be included in the screening processes for the monoclonals, including making the patient aware of the risk versus benefits of the treatment options at hand. In general, the monoclonals appear to be safe for pregnant or breastfeeding mothers. You can read more about this topic here in the January 2022 Joint Statement from MDH, MN ACOG, Allina Health, Mayo Clinic, and University of Minnesota statement on COVID-19 Monoclonal Antibody Use in Pregnancy.
O is for Oxygen
For those monoclonals only approved for use in mild-moderate COVID-19, note that an Sp02 below 94% due to COVID-19 puts a patient in the category in severe or critical COVID-19. Therefore, when used for treatment, a pre-dose oxygen saturation may be considered to confirm qualification.
..maybe O should have been for Omicron?… as in what is Omicron going to do next and how will that impact which monoclonal antibodies we can use???
Q is for FAQ
Many people access the HCP Fact Sheets, but the FAQs associated with each monoclonal antibody have also been super helpful with practice application of when these treatments can be used or navigating nuances. For example, find the sotrovimab FAQ here, which answers questions such as: “Does the EUA permit the use of sotrovimab as authorized in patients hospitalized for reasons other than COVID-19?”
R is for Route
Tixagevimab/cilgavimab is only indicated to be given via intramuscular injection. Bebtelovimab is authorized to be given via IV push. Sotrovimab is authorized to be given IV over as short as 15 minutes. Casirivimab/imdevimab was authorized for intravenous or subcutaneous administration, with intravenous preferred for treatment and subcutaneous preferred for post-exposure prophylaxis.
The route of administration is not only variable across the monoclonal antibody arsenal, the route and administration instructions have also been known to be modified in the HCP Fact Sheets.
S is for Stewardship
A recent study of sotrovimab found use is associated with rapid development spike gene mutations and is associated with sotrovimab resistance. This led authors to call for stewardship for monoclonal antibodies. Just like antibiotics it appears this is a “the more you use it, the more you lose it” type of situation. In the aforementioned study, patients treated with sotrovimab had SARS-CoV-2 isolated up to 24 days after treatment!
T is for Timing
When it comes to treatment of COVID-19, both sotrovimab and bebtelovimab EUAs require treatment with 7 days of symptom onset. Previously for bamlanivimab, bamlanivimab/etesevimab, and casirivimab/imdevimab it was 10 days. It makes sense that a therapy which impacts viral replication be given early in the disease when the virus is replicating the most, but it also makes it challenging to communicate ever-changing criteria when what was once 10 is now 7.
Timing will also matter for re-dosing of pre-exposure prophylaxis tixagevimab/cilgavimab, as mentioned above in the kinetics section.
U is for Utility
Different therapies have different utility and this must always be taken in the context of the individual patient factors along with which variants are likely prevalent.
The NIH COVID-19 guidelines rank preference in treatment options of non-hospitalized patients with COVID-19 as: PO nirmatrelvir/ritonavir (Paxlovid) x5 days > IV sotrovimab (Xevudy) once > IV remdesivir (Veklury) x3 days > PO molnupiravir (Lagevrio) x5 days = IV bebtelovimab once.
With the oral therapies becoming more readily available, it is possible (if not likely), that SARS-CoV-2 monoclonal antibody utility will become less.
V is for Verification of Documentation & Eligibility
Verification of key EUA information should be considered to be built into the workflow of monoclonal antibody ordering, dispensing, and administration. All of the EUAs require that “through a process of inventory control, healthcare facilities will maintain records regarding the dispensing and administration of for the use authorized in this letter (i.e., lot numbers, quantity, receiving site, receipt date), product storage, and maintain patient information (e.g., patient name, age, disease manifestation, number of doses administered per patient, other drugs administered.)” To ensure this is done, a verification workflow may be worth pursuing and regularly revising.
W is for Workflow
Monoclonal antibody programs had to be stood up from scratch for many (if not all?) healthcare organizations. Depending on the indication and EUA requirements, that may impact the workflow on referrals, assessments, prioritization, the patient experience, and more. This becomes all that much more difficult when we add on pandemic surges which cause site capacity to administer and drug availability to wax and wane. Don’t forget to also consider the billing (for the administration) part which is not super straight forward or static. Billing CDM codes can be found here in case you need them. It really goes way beyond just verification and documentation workflows.
X, Y, and Z are XYZ
What is XYZ? Well it’s gibberish, just like some of how these monoclonal antibody names sound! It took me months to master “bamlanivimab” which is now of no help at all. Which ridiculous name will we need to familiarize ourselves with next? At least I hope you are having fun with the names as we try to twist our tongues to pronounce them.
Disclosure: The views and opinions in this article are that of the author and do not necessarily reflect the opinion or policy of any former, current, or potential future employer.
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