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Introduction

The impressive efforts of the medical and scientific communities in response to the challenges of the coronavirus disease 2019 (COVID-19) pandemic have rapidly produced a range of vaccines and therapeutics to help prevent infections and treat patients. In this continuing education activity, the focus will be on the monoclonal antibodies (mAbs) subset of therapeutics for treating COVID-19. At the onset of preparing this activity, the US Food and Drug Administration (FDA) granted emergency use authorizations (EUA) to 3 mAb treatment regimens and a mAb preventative therapy. Since then, the emergence and eventual dominance of the omicron variant, as described herein, the FDA modified the EUAs for two of the regimens such that their accepted use has been severely curtailed.

Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that leads to coronavirus disease 2019 (COVID-19) typically produces mild or asymptomatic disease. For a sizable number of infections, patients may experience moderate-to-severe disease that can necessitate advanced life-saving measures and can lead to death.¹ Li et al in their systematic review and meta-analysis estimated that 22.9% (95% CI, 13.3%-36.5%) of COVID-19 cases had severe disease and that 5.6% (95% CI, 4.2%-7.5%) of cases resulted in mortality.² Country- and region-specific variations were also observed within the areas studied where Wuhan, China, exhibited the highest percentage of severe disease (37.9%; 95% CI, 29.6%-46.96%) and Italy presented the highest mortality rate (14.3%; 95% CI, 4.2%-39.2%).² The percentages should be expected to change as the pandemic continues; treatment regimens are developed and refined; vaccination rates increase; and subsequent variants emerge. Tracking websites, such as the Coronavirus Resource Center of Johns Hopkins University, can provide current data (eg, cases, deaths, vaccinations, etc) on the pandemic.³

Given the rapidly changing landscape of the ongoing COVID-19 pandemic, readers should note that new data, recommendations, and guidelines may change the details of drug information provided herein. Every effort was made to ensure information in this activity is current at the time of publication. Worldwide research efforts on SARS-CoV-2 produce new data daily, which can lead to rapid changes in treatment guidelines. The urgency of the ongoing research leads to some information being published on a preprint basis prior to full peer review. Balancing the need for understanding with critical review can be a challenge. Clinicians should be aware of these challenges when evaluating data.

The ongoing COVID-19 pandemic has affected every nation³ and virtually every aspect of modern society. As of February 8, 2022, more than 388 million cases of COVID-19 have been confirmed worldwide with over 5.7 million deaths. The United States accounts for over 76 million cases and over 900 000 deaths.³ The scale of the pandemic, the related mortality and morbidity, and the impact on society are difficult to minimize. Staying up-to-date with the current state of the pandemic and with treatment options for COVID-19 will help ensure that clinicians can continue to provide excellent health care to patients.

Inflammatory Profile of COVID-19

SARS-CoV-2, like other disease-causing coronaviruses, affects the respiratory system, primarily in the lower respiratory tract leading to pneumonia.⁴ Early in the pandemic, clinicians determined that a hyperinflammatory syndrome appeared to be associated with severe cases of COVID-19.⁵ A number of studies subsequently described a multitude of cytokines, Natural Killer (NK) cells, and other markers that were associated with hyperinflammation. The systematic review and meta-analysis by Qin and colleagues detail the factors that describe the inflammatory profile of severe COVID-19 with 145 studies as the basis for their analysis.⁶ In patients who had severe COVID-19 or who died from the illness, numerous cytokines were found to be elevated, particularly the interleukins (IL) -1β, -1Ra, -2R, -4, -6, -8, -10, -18; tumor necrosis factor alpha (TNF-α); and interferon gamma (IFN-γ).⁶ The pattern of elevated cytokines (sometimes referred to a “cytokine storm”) provides clues to the mechanisms of hyperinflammation and related consequences of severe COVID-19 disease.⁷

Mechanisms of hyperinflammation

In mild cases of COVID-19, innate and adaptive immune responses coordinate so that the offending virus can be cleared from the body. Macrophages, dendritic cells, and NK cells dominate the innate immune response leading to the adaptive response, which involves the recruitment of CD8+ and CD4+ T cells and maturation of B cells to produce longer lasting immunity through virus-specific antibodies.⁷ In severe cases of COVID-19, it appears that a delay in early interferon release within a dysregulated innate immune response leads to excessive cytokine production (ie, cytokine storm).⁷ Other hallmarks of hyperinflammation include increased activation of macrophages, decreased NK cell response, and increased T helper cells.¹ The hyperinflammation driven by an abnormal immune system response in severe COVID-19 cases can progress to coagulation dysfunction, thrombosis, and organ damage to the lungs and other organs.^1,6,7

Comparison to other viral respiratory conditions

The hyperinflammation and related cytokine storm observed in severe COVID-19 bear similarities to features of other conditions such as viral-induced or familial hemophagocytic lymphohistiocytosis and macrophage activation syndrome.^1,7 Persons with COVID-19 experiencing hyperinflammation may progress to multisystem inflammatory system (MIS-A in adults; MIS-C in children).⁸ In children with COVID-19, MIS-C bears resemblance to toxic shock syndrome, Kawasaki disease, and the aforementioned hemophagocytic lymphohistiocytosis and macrophage activation syndrome.¹ Symptoms of MIS-A and MIS-C include ongoing fever and one or more of the following: gastralgia, conjunctivitis, diarrhea, vertigo or lightheadedness, dermatitis, and/or emesis.⁸

Disease burden of COVID-19

Impact across the United States
The COVID-19 pandemic has affected practically every aspect of modern life from the societal level (eg, public health, the economy, travel, politics, etc) to the individual and family levels (eg, physical activity, personal interactions, mental and physical health, etc). Health, environmental, and socioeconomic disparities have led to marginalized populations (eg, people of color, undocumented individuals, LGBTQ(+) individuals, underserved, etc) being more adversely affected by the pandemic.^9,10 The arrival of COVID-19 vaccines first by EUA and then by full FDA approval ushered in new tools to prevent infections, severe illnesses, and deaths due to COVID-19. Even with the most recent variant (omicron B.1.1.529), early reports suggest that available vaccines retain efficacy against the variant.^11,12 Preventing illness/disease via vaccinations and other public health measures will continue to be the most effective approach to combating the pandemic. Therapeutic interventions for the treatment of COVID-19 are still clearly necessary, since no vaccine is 100% effective.

Interventions that can reduce hyperinflammation or modify immune response

Several options are available to treat the hyperinflammatory response in severe cases of COVID-19. The WHO and NIH provide updated recommendations for the use of such therapeutics.^13,14 The recommendations differ based on specific patient criteria (eg, severity of disease, need for supplemental oxygen, hospitalization status, etc) and the particular recommendations for each scenario are beyond the scope of this activity. The available options can be grouped into systemic corticosteroids (dexamethasone, hydrocortisone, methylprednisolone, prednisone), IL-6 inhibitors (sarilumab, tocilizumab, siltuximab), Janus kinase (JAK) inhibitors (baricitinib, tofacitinib), antivirals (remdesivir, ritonavir, and nirmatrelvir), preventative monoclonal antibodies (tixagevimab/cilgavimab), and monoclonal antibodies for treatment (next section).^13,14

Monoclonal Antibody Treatment for COVID-19

Mechanisms of mAb treatment

Targeting the spike protein on the surface of SARS-CoV-2 virus
One of the most effective approaches to treat ongoing viral infections is to prevent the virus from attaching to cells. The composition of coronaviruses typically includes four types of structural proteins: spike (S) protein, envelope protein, membrane protein, and nucleocapsid protein.¹⁵ The S protein of SARS-CoV-2 binds to the cell surface protein, angiotensin converting enzyme 2 (ACE2), leading to cell attachment, entry of virus into the cell, and fusion between the viral membrane and cell membrane.^15,16 Once the virus enters the cell and fuses with the cell membrane, the viral RNA is released into the cytoplasm leading to continued virus production.¹⁵

The S protein of SARS-CoV-2 is the main target of available mAbs treatments since the protein appears on the surface of the virus and is integral to cellular entry. Binding of mAbs to the S protein blocks or hinders virus attachment at ACE2. The S protein consists of two subunits; the S1 subunit is responsible for virus binding and the S2 subunit is responsible for virus-cell fusion.^15–17 The available mAb drugs bind to regions of the S1 subunit of SARS-CoV-2 to either block virus attachment at ACE2 (ie, bamlanivimab, etesevimab, casirivimab, and imdevimab) or neutralize SARS-CoV-2 (ie, sotrovimab).¹⁸

What is the ACE2 binding site? How does this affect mutations?
Binding of SARS-CoV-2 to the ACE2 receptor occurs via the receptor binding domain (RBD) located on the S1 subunit.¹⁸ mAbs that target the RBD prevent binding of virus to the receptor since this is the initial step in cellular uptake.^19–21 The ACE2 RBD, however, is a major site of virus mutations via deletion, insertion, or point mutations in the S protein genome.²² Therefore, changes in the RBD can affect binding of virus to the receptor and binding of therapeutic mAbs to the S1 subunit. Bamlanivimab, etesevimab, casirivimab, and imdevimab directly inhibit virus-receptor binding by targeting the RBD. Sotrovimab, on the other hand, binds to an evolutionarily conserved epitope of the RBD to prevent virus fusion to cell membrane via a mechanism that is not fully clear.^23,24

Impact of variants on mAb efficacy
Virus variants occur based on natural mutations and these mutations may affect virus transmissibility and/or infectivity as well as disease severity and reduced efficacy of therapeutics and vaccines. Single-stranded RNA viruses, such as SARS-CoV-2, typically have faster mutation rates than other types of viruses.²⁵ Changes in the virus genome are subsequently translated to changes in amino acid sequences and structure of the target protein. Since mAbs target specific amino acid sequences or protein structures, such changes may lead to altered efficacy. The US SARS-CoV-2 Interagency Group delineates variants of SARS-CoV-2 into four classes of increasing public health magnitude – Variant Being Monitored, Variant of Interest, Variant of Concern, and Variant of High Consequence.²⁶ The most recent Variant of Concern, omicron (B.1.1.529), has presented challenges to mAb efficacy. Testing has demonstrated that bamlanivimab/etesevimab and casirivimab/imdevimab are not effective against omicron and, therefore, EUA for these drugs has been curtailed. On the other hand, sotrovimab has retained sufficient activity against omicron and the drug remains a recommended treatment for COVID-19 caused by the variant.^27,28 New variants will continue to emerge and the efficacy of available treatments will need to be determined particularly if the variants become a public health concern.

Available mAbs: Summary of clinical trials, current status of authorization/use

bamlanivimab plus etesevimab²⁹
Bamlanivimab and etesevimab are mAbs developed based on antibodies isolated from patients who recovered from COVID-19.^19,20,30 Bamlanivimab and etesevimab bind to different regions of the S1 RBD.^19,20 Bamlanivimab, originally tested as a single agent, demonstrated greater efficacy when used in combination with etesevimab. As will be seen with another of the mAb treatments, combination treatments can be a helpful approach to improve efficacy.

The FDA originally granted EUA on February 9, 2021, to bamlanivimab plus etesevimab for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients (≥ 12 years of age, ≥ 40 kg body weight) who have a positive result in a SARS-CoV-2 viral test and who are at high risk for progressing to severe COVID-19 and/or hospitalization. The FDA has made several modifications to the EUA over time most recently on January 24, 2022.³¹ The BLAZE-1 clinical trial provided the data on which EUA was granted. In the phase 2/3 portion of BLAZE-1, nonhospitalized adult patients with mild-to-moderate COVID-19 (n = 577) received either bamlanivimab monotherapy (700 mg, 2800 mg, or 7000 mg), bamlanivimab plus etesevimab (2800 mg of each), or placebo. Treatments or placebo were given as single, 1-hour intravenous infusions. The primary end point of the study was the change in viral load (measured as log viral load) at day 11 (± 4 days) postinfusion. Of the four treatment groups described, only the combination therapy demonstrated statistically significant reduction in log viral load compared to placebo. The difference in the change in log viral load at day 11 for bamlanivimab plus etesevimab (2800 mg of each) vs placebo was -0.57 (95%CI, -1.00 to -0.14; P = 0.01). The three other treatment groups were bamlanivimab monotherapy at different doses, for which the differences in the change in log viral load at day 11 were 0.09 (95%CI, -0.35 to 0.52; P = 0.69) for 700 mg; -0.27 (95%CI, -0.71 to 0.16; P = 0.21) for 2800 mg; and 0.31 (95%CI, -0.13 to 0.76; P = 0.16) for 7000 mg. Adverse events unrelated to COVID-19 were minimal with nausea and diarrhea being the most common such events. Two severe adverse events were observed: a urinary tract infection in the combination treatment group and upper abdominal pain in the placebo group. Both serious adverse events were deemed unrelated to the study drug or placebo. In addition, several immediate hypersensitivity reactions considered possibly infusion related were reported with 6 people in the bamlanivimab monotherapy group, 2 people in the combination mAb group, and 1 person in the placebo group. As noted by the investigators, reactions were considered mild and did not stop completion of the infusions.³⁰

Dougan et al reported results from a cohort of adolescent (≥ 12 years old) and adult patients (n = 1035) in a double-blind, randomized, placebo-controlled phase 3 clinical trial with a primary end point of Covid-19-related hospitalization or death from any cause by day 29. The results showed that 2.1% of patients in the bamlanivimab/etesevimab treatment group had a COVID-19-related hospitalization with no deaths. On the other hand, 7.0% of patients in the placebo cohort had a hospitalization or death related to COVID-19 (10 deaths in the group with 9 attributed to COVID-19). The statistical analysis determined an absolute risk difference of -4.8% (95% CI, -7.4 to -2.3) with a relative risk difference of 70% (P < 0.001). The rates of serious adverse events were similar between the cohorts: 1.4% and 1.0% for bamlanivimab/etesevimab and placebo, respectively. Similarly, the rates of all adverse events were similar; 13.3% for the bamlanivimab/etesevimab group compared to 11.6% in the placebo group with nausea, rash, and dizziness being the most common adverse events.³²

Similar results in risk reduction were observed at lower doses of bamlanivimab/etesevimab. When bamlanivimab (700 mg) and etesevimab (1400 mg) was compared to placebo within the BLAZE-1 trial, 4 out of 511 patients (0.8%) receiving the drug combination had a primary outcome (COVID-19-associated hospitalization or all-cause death) compared to 15 out of 258 patients (5.8%) receiving placebo for an absolute risk reduction of -5% (95% CI, -8.0 to -2.1; P < 0.001). No deaths were observed in the bamlanivimab/etesevimab group while 4 COVID-19-related deaths occurred in the placebo group.³³

casirivimab plus imdevimab³⁴
The mAbs, casirivimab and imdevimab, used in another combination therapy were identified via high throughput screening for activity at separate, nonoverlapping regions of the SARS-CoV-2 S protein.²¹ The FDA granted EUA on November 21, 2020, for casirivimab and imdevimab for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients (≥ 12 years of age, ≥ 40 kg body weight) with a positive SARS-CoV-2 viral test result who are at high risk for progressing to severe COVID-19 and/or hospitalization. The FDA has made several modifications to the EUA over time most recently on January 24, 2022.³¹ Data from the REGEN-COV trial served as a basis for the EUA. The REGEN-COV study is a phase 1-3 adaptive clinical trial with casirivimab plus imdevimab as the study drug. Each phase was run as randomized, double-blind, placebo-controlled trials. After exhibiting efficacy in phase 1 and 2 portions of the REGEN-COV trial, the phase 3 part continued. The adaptive nature of the trial permitted changes in dosages and randomization based on ongoing results, and results from the adult patient cohort (≥ 18 years old) at doses of 1200 mg, 2400 mg, and placebo have been reported with primary end points of Covid-19–related hospitalization or death from any cause.²⁷ Drug or placebo was administered via intravenous infusion. The primary end point was reached in 7 out of 736 patients (1.0%; 6 hospitalizations, 1 death) for the 1200 mg group and in 24 of 748 patients in the concurrently randomized placebo group (3.2%; 23 hospitalizations, 1 death) for a relative risk reduction of 70.4% (P = 0.002). The primary end point was reached in 18 of 1355 patients (1.3%; 17 hospitalizations, 1 death) for the 2400 mg group and in 62 of 1341 patients in the concurrently randomized placebo group (4.6%; 59 hospitalizations, 3 deaths) for a relative risk reduction of 71.3% (P = 0.001). At either dose of casirivimab plus imdevimab, the median time to resolution of symptoms was shorter compared to placebo: 10 days for either treatment group; 14 days for placebo groups, P < 0.001. In regards to serious adverse events, both treatment groups had lower rates (1.1% for 1200 mg; 1.3% for 2400 mg) compared to 4.0% for the placebo group, while < 0.3% of patients across all treatment and placebo groups experienced infusion-related reactions (grade 2 or higher).²⁷

sotrovimab²⁴
While sotrovimab is a human mAb that also binds to the SARS-CoV-2 S1 subunit, the mAb targets an evolutionarily conserved section RBD of the S1 subunit that does not interfere with the virus binding to the ACE2 receptor.^23,35,36 The FDA granted EUA on May 26, 2021, for sotrovimab for the treatment of mild to moderate COVID-19 in adults and pediatric patients (≥ 12 years of age, ≥ 40 kg body weight) with a positive SARS-CoV-2 viral test result who are at high risk for progressing to severe COVID-19 and/or hospitalization. The FDA has made modifications to the EUA over time most recently on December 16, 2021.³⁷ The COMET-ICE trial has provided data for the basis of the EUA. A double-blind, placebo-controlled trial, COMET-ICE has studied sotrovimab (500 mg) compared to placebo with the primary outcome of hospitalization (any cause) or death within 29 days after randomization. At a predetermined interim analysis of data, trial investigators reported that patients receiving sotrovimab had a relative risk reduction of 85% (97.24% CI, 44-96; P = 0.002) compared to patients in the placebo arm of the study. In the 291 sotrovimab-treated patients analyzed, 3 patients (1%) were hospitalized for any cause and no deaths were observed. For the placebo group (n = 292), 21 patients (7%) were hospitalized (one of whom died). Rates of adverse events including serious adverse events were similar between the two groups. Adverse events were reported in 17% of sotrovimab-treated patients and 19% in the placebo-treated cohort while serious adverse events were reported in 2% of sotrovimab-treated patients and 6% in the placebo group.³⁸ Table 1 summarizes the available COVID-19 mAb therapies.

With the onset of the omicron variant (B.1.1.529), the efficacies of bamlanivimab plus etesevimab and casirivimab plus imdevimab have waned substantially to the point where FDA updated their EUAs. As a result of the dominance of the omicron variant, the drug combinations are not currently authorized for use within the United States. Sotrovimab has retained efficacy against the omicron variant and its EUA allows for continued use in the United States.³¹

Strategies for Integrating mAb Treatment Into Clinical Care for COVID-19

Patient selection and comorbidity management

Definition of at-risk adult
Certain patient populations appear to be at higher risk for the development of severe COVID-19 disease, which can lead to serious health complications such as the need for mechanical ventilation and death. Groups that are at increased risk of severe illness and/or death include adults older than 65 years, people with disabilities, and people of color.³⁹ In addition, the CDC has identified certain medical conditions that can increase a person’s risk of severe COVID-19 illness and/or death due to COVID-19 particularly if the person has more than one listed condition. The medical conditions are listed in Table 2.³⁹

Definition of at-risk child
In addition to criteria for at-risk adults, the CDC outlines criteria for at-risk children. Generally, children with underlying medical conditions or with medical complexity are at greater risk of severe COVID-19 illness. Such conditions include (in alphabetical order): chronic lung disease (including asthma), congenital heart disease, diabetes, genetic disorders, immunosuppression, metabolic disorders, neurologic disorders, obesity, and sickle cell disease.³⁹ For younger children, the risk is exacerbated due to lack of eligibility for vaccination.

Treatment selection, including impact of emerging resistance

Dosage, administration (when to start treatment)
Selection of mAb treatment options is based on patient risk of developing severe COVID-19 illness. The COVID-19 Treatment Guidelines Panel of the NIH maintains and updates treatment guidelines. In the most recent update of February 1, 2022, the Panel recommended the following pharmacotherapy options for high-risk, nonhospitalized patients with mild-to-moderate COVID-19 (in order of preference): (A) “Nirmatrelvir 300 mg with ritonavir 100 mg (Paxlovid) orally twice daily for 5 days, initiated as soon as possible and within 5 days of symptom onset in those aged ≥ 12 years and weighing ≥ 40 kg;” (B) “Sotrovimab 500 mg as a single IV infusion, administered as soon as possible and within 10 days of symptom onset in those aged ≥ 12 years and weighing ≥ 40 kg;” (C) “Remdesivir 200 mg IV on day 1, followed by remdesivir 100 mg IV daily on days 2 and 3, initiated as soon as possible and within 7 days of symptom onset in those aged ≥ 12 years and weighing ≥ 40 kg;” and (D) “Molnupiravir 800 mg orally twice daily for 5 days, initiated as soon as possible and within 5 days of symptom onset in those aged ≥ 18 years ONLY when none of the above options can be used.”⁴⁰ As described above in this activity, the emergence of variants with resistance to current therapeutics can lead to changes in these recommendations as was recently done with the omicron variant.

Safety issues

Adverse events and drug-drug interactions
mAbs in general and the SARS-CoV-2 mAbs in particular are not expected to exhibit drug-drug interactions since they are not excreted renally nor do they interact with major drug metabolizing enzymes (eg, CYP 450) as substrates, inducers, or inhibitors.^24,29,34 To date, adverse events have been fairly minimal, and, as reported in the clinical trials, adverse events from bamlanivimab/etesevimab, casirivimab/imdevimab, or sotrovimab were generally similar between the treatment and placebo cohorts.^27,32,33,38 The relatively mild adverse event profile of these mAb treatments may be related to their mechanism of action – binding to a target viral protein.⁴¹

Hypersensitivity reactions
Protein-based therapeutics, such as mAbs, however, are known to have propensities to induce serious, hypersensitivity reactions (eg, anaphylaxis) and infusion-related reactions, which are highlighted in the EUAs for the mAbs discussed.^24,29,34 Administration of the drugs should be immediately discontinued if signs and symptoms of hypersensitivity or anaphylaxis reactions are observed. Infusion-related reactions can occur during drug administration as well as up to 24 hours postinfusion. Decreasing the infusion rate or discontinuing the infusion may be necessary if an infusion-related reaction occurs. In addition, standard treatment protocols for anaphylaxis or infusion-related reactions should be applied to treat patient’s acute symptoms. Health care providers or their designee are responsible to report any serious adverse event, including any life-threatening adverse events, to FDA MedWatch per the EUA of all mAbs.^24,29,34 Furthermore, as acknowledged by the manufacturers, additional adverse events including serious events may be revealed as additional clinical data are generated for bamlanivimab/etesevimab, casirivimab/imdevimab, and sotrovimab.^24,29,34

Breastfeeding mothers
Due to the limited clinical data in general and in breastfeeding mothers in particular, there is insufficient information on the use of the bamlanivimab/etesevimab, casirivimab/imdevimab, or sotrovimab during lactation. The large molecular weight of these mAbs (generally > 144 kDa) suggests that infant exposure would likely be very low since excretion in breast milk is likely to be minimal and absorption from the infant’s gastrointestinal tract would be similarly minimal.^42–46 Regardless, until sufficient data are generated, use of these mAbs in lactating women should proceed with caution.

Considerations for pharmacists in mAb implementation for COVID-19

Patient education

Just as the COVID-19 pandemic has upended and altered multiple aspects of modern life, the roles of pharmacists have also evolved. Throughout the pandemic, as hospitals became overwhelmed with patients during pandemic surges, pharmacists stepped into new roles or expanded established roles.^47-49 Pharmacists should be prepared to continue their role as drug information experts with respect to current and emerging COVID-19 mAb treatments, especially for formulations delivered subcutaneously. In addition to being a resource for health care professional colleagues, pharmacists are key players in patient education. Providing the most accurate and current information to patients is critical as guidelines and recommendations can change rapidly. The widespread misinformation campaigns surrounding COVID-19 have created unique challenges for patient education.^50,51

Drug-drug interactions and mitigation of adverse events

As discussed above, drug interactions have not been observed for the COVID-19 mAbs and they are not expected to be an issue due to lack of renal elimination and lack of interaction with metabolizing enzymes. Regardless, maintaining awareness of possible drug interactions is essential. Likewise, the adverse event profiles of the mAbs have been mild. Overall, the management of COVID-19 mAb infusion services require substantial coordination between multiple stakeholders, including pharmacists, in order to provide high-quality, effective patient care.^52–54 In addition to participating in those coordination efforts, pharmacists should be prepared to report and respond to adverse events. As indicated in the EUAs for the mAb drugs, serious adverse events must be reported to the FDA MedWatch program via an online form (www.fda.gov/medwatch/report.htm), a hard copy form (https://www.fda.gov/media/76299/download) to be mailed or faxed, or telephone (1-800-FDA-1088) to request a form. The EUAs specify serious adverse events as “death; a life-threatening adverse event; inpatient hospitalization or 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; a medical or surgical intervention to prevent death, a life-threatening event, hospitalization, disability, or congenital anomaly.”^24,29,34

Summary

As the COVID-19 pandemic moves beyond the 2-year point, advances in pharmacotherapy continue to be developed at a rapid pace. Staying current on recommended treatment options can help ensure that clinicians provide the best care to patients. Emergence of new SARS-CoV-2 variants will likely continue and susceptibility of variants to available drugs will need to be evaluated. Due to the urgency of the pandemic, the FDA has made many drugs available via EUA. Those authorizations can change based on drug efficacy against emergent variants. Monoclonal antibody treatments are one class of pharmacotherapy options for nonhospitalized patients with COVID-19 who do not require supplemental oxygen and who have a high risk of progression to severe disease. Other drugs classes are also available for patients who fit these criteria. The available mAbs target the S1 subunit of the SARS-CoV-2 S protein that binds to cell surface ACE2 receptor prior to cell entry. Two mAbs treatment options for non-hospitalized patients are combination therapies (ie, bamlanivimab/etesevimab, casirivimab/imdevimab) both of which unfortunately have been rendered ineffective against the currently circulating SARS-CoV-2 variant, omicron. Bamlanivimab, etesevimab, casirivimab, and imdevimab inhibit virus-receptor binding by targeting the RBD of the S1 subunit, a section of protein that is highly susceptible to mutations. Another mAb treatment, sotrovimab, binds to an evolutionarily conserved epitope of the RBD to prevent virus fusion to cell membrane. Sotrovimab has retained efficacy against the omicron variant. This activity introduces the reader to the currently available mAb treatment options for nonhospitalized patients with COVID-19 who are at high risk of progressing to severe disease.

References

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