Year: 2021
Type: article
Abstract: (See the Major Article by Ganesh et al on pages 1278–86.) As the coronavirus disease 2019 (COVID-19) pandemic continues, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 ) variants with potential for increased transmissibility and severity of illness [1, 2], such as the B.1.1.7 (alpha), B.1.617.2 (delta), and P.1 (gamma) variants, have sustained transmission in the community and disproportionately affect unvaccinated persons [3]. Other than providing supportive care, counseling on COVID-19 transmission risk reduction, and monitoring for disease progression [4], the only therapeutics for outpatient management of COVID-19 are neutralizing monoclonal antibodies directed to SARS-CoV-2 spike protein, made available through the US Food and Drug Administration (FDA) emergency use authorization (EUA) [5–8]. Four products have been made available for the treatment of mild to moderate COVID-19 in persons at high risk for severe disease. Emergency use authorization of bamlanivimab (approved November 9, 2020 [revoked April 16, 2021]) [5, 9], casirivimab-imdevimab (approved November 21, 2020) [6], bamlanivimab-etesevimab (approved February 9, 2021) [7], and sotrovimab (approved May 26, 2021) [8] was based on the following: early clinical trials data demonstrating reductions in SARS-CoV-2 viral load [5–7, 10, 11]; hospitalizations and emergency department (ED) and/or medically attended visits [5–8, 10–12]; and deaths [7] in those who receive therapy versus placebo early in the course of clinical symptoms. To date, there have been no comparative trials of the different monoclonal antibody preparations, and, because of this, there have been no clear differences in indication or treatment outcomes among these agents. To the same end, the EUA eligibility criteria are the same for each product. In this issue of the Journal of Infectious Diseases, Ganesh et al [13] provide important postclinical trial experience with the first neutralizing monoclonal antibody treatments for COVID-19, available through FDA EUA, and the first study comparing outcomes of persons who receive bamlanivimab versus casirivimab-imdevimab. In this observational, retrospective study design, 3596 adult patients with laboratory-confirmed mild to moderate COVID-19 and ≤10 days of symptoms met EUA eligibility criteria for monoclonal antibody treatment and received an infusion of either bamlanivimab or casirivimab-imdevimab, based on product availability at the infusion facility. All patients had a last 1 underlying condition that placed them at risk for progressing to severe COVID-19, and 55.3% had multiple comorbidities as measured by a Monoclonal Antibody Screening Score (MASS) that assigned weighted points based on number and relative risk of EUA high-risk eligibility criteria met by the patients [14, 15]. For the primary study outcome, there were lower rates of 28-day, all-cause hospitalization in persons who received casirivimab-imdevimab compared with those who received bamlanivimab (2.83% v. 4.34, P = .05); however, antibody treatment groups were not comparable in terms of underlying high-risk medical conditions. Patients who received bamlanivimab were more likely to have hypertension (53.3% vs 48.3%, P = .01) and a higher burden of comorbid medical conditions as indicated by distribution of the MASS between the antibody treatment groups (P = .008). Ultimately, in the proportional hazards regression model, bamlanivimab-treated patients had a higher likelihood of hospitalization versus casirivimab-imdevimab-treated patients (unadjusted hazard ratio [HR] = 1.5; 95% confidence interval [CI], 1.0–2.4; P = .05), but when adjusted for the MASS, this did not reach statistical significance (adjusted HR, 1.4, 95% CI, 0.9–2.2; P = .12). In the proportional hazards regression model, those in the bamlanivimab-treatment group also had a higher likelihood of COVID-19-related, 28-day hospitalization compared with those treated with casirivimab-imdevimab (unadjusted HR 1.7; 95% CI, 1.0–3.1; P = .05), but this also did not reach statistical significance once adjusted for the MASS (adjusted HR, 1.6; 95% CI, 0.8–2.7; P = .13). There were no significant differences between the treatment groups in secondary outcomes such as rates of ED visits, admissions to the intensive care unit, or deaths. The Mayo Clinic experience adds to the growing body of reports demonstrating reduced hospitalization rates in persons who received a neutralizing monoclonal antibody infusion for COVID-19. Other real-world studies have demonstrated hospitalization risk reduction of 50% in persons treated with either bamlanivimab or casirivimab-imdevimab and 64% in persons treated with bamlanivimab compared with historical and contemporary controls, respectively [16, 17]. The Mayo cohort and other reported real-world outcomes compare favorably with clinical trials data, with relative hospitalization risk reduction of 67% and 70% with bamlanivimab in all versus high-risk subjects [5], 50% and 67% with casirivimab-imdevimab in all versus high-risk subjects [6], 87% with bamlanivimab-etesevimab [7], and 85% with sotrovimab [8]. The current and other real-world study results are especially promising given that they were achieved in patient cohorts with higher comorbidity burden compared with participants of the early bamlanivimab and casirivimab-imdevimab clinical trials. However, it remains uncertain whether these results are generalizable in patients who have significant underlying medical comorbidities, and, perhaps, this is an area in which differences in efficacy may emerge among the available neutralizing antibodies. In the current study, high comorbidity burden, as measured by the MASS, was associated with 28-day, all-cause hospitalization rate. In addition, chronic kidney disease, immunocompromised status, cardiovascular disease, and chronic lung disease were associated with all-cause hospitalization, whereas higher body mass index was associated with lower risk for hospitalization. Similarly, Kumar et al [17] identified higher median comorbidity burden (measured by a cumulative priority system sum), presence of chronic kidney disease, age >55 years with hypertension, age >55 years with cardiovascular disease, and age >55 years with chronic lung disease as univariate predictors of 30-day hospitalization. In 2 small series reporting outcomes of organ transplant recipients with COVID-19 treated with bamlanivimab monotherapy, higher rates of hospitalization (16.7% in both) were observed [18, 19]. Clinical trials and real-world studies were conducted before the emergence of variants such as Beta (B.1.351), Delta (B.1.617.2), Gamma (P.1), and Zeta (P.2). Each of these variants carries 1 or more amino acid substitutions in the receptor binding domain (RBD) of the SARS-CoV-2 spike protein [1]. These circulating variants present the greatest threat to the efficacy of COVID-19 monoclonal antibody therapies, and it is in this context that differential activity of the available monoclonal antibodies is emerging. With B.1.35, P.1, and P.2, the E484K substitution results in loss of neutralizing activity of bamlanivimab and reduced activity of bamlanivimab-etesevimab [20, 21]. The Delta variant, B.1.617.2, possessed 2 RBD substitutions, E484Q and L452R, that render bamlanivimab and bamlanivimab-etesevimab inactive [22]. Because of concerns for loss of neutralizing activity potentially leading to treatment failures, the FDA revoked the EUA for bamlanvimab; in addition, bamlanivimab-etesevimab is no longer recommended for use in the United States because of variants with reduced susceptibility [9, 23]. Casirivimab-imdevimab and sotrovimab have retained activity against all circulating variants of SARS-CoV-2 and remain recommended treatments for mild to moderate COVID-19 [20–23]. Casirivimab and imdevimab bind to non-overlapping epitopes of the RBD [6], and this confers some protection from a single mutation resulting in loss of activity. For example, B.1.351 and P.1 variants, casirivimab has reduced activity, but the activity of imdevimab is preserved [20, 21]. Although sotrovimab is infused as a monotherapy, this antibody binds to a more conserved region of the spike protein RBD [8], and, thus, it is less vulnerable to substitutions that occur in the RBD. The study reported by Ganesh et al [13] adds to the growing body of evidence that outside of clinical trials these monoclonal therapies, when given early and to specific patient subgroups, offer an effective means of keeping patients out of the hospital and from progressing to severe COVID-19. The current study highlights differences in outcome with these therapies based on multiple comorbidities, which may allow clinicians to focus therapy on these higher risk groups. Limitations remain in these studies, which lack traditional control groups and have not accounted for the spread of monoclonal antibody-resistant variants. Future studies should focus on newer monoclonal antibodies more resistant to viral change, comparisons of treated and untreated and untreated populations, and the utility of these therapies in inpatient populations and as a prophylactic measure. The Mayo Clinic experience adds to the growing evidence that monoclonal antibody therapy is effective for outpatient management of SARS-CoV2 infection, and clinicians should be reassured that these therapies work and that they should offer them to their eligible patients. Potential conflicts of interest. V. S. reports research grant from Eli Lilly and Company paid to Northwestern University and honorarium from Med Learning Group for educational lectures about coronavirus disease 2019 monoclonal antibodies. M. P. A. reports honoraria from DKBMed for Allergan Pharmaceuticals for educational lectures and consulting fees from Abbvie Pharmaceuticals. He participates in the Data and Safety Monitoring Board for Abbvie Pharmaceuticals. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
Authors: Valentina Stosor, Michael P Angarone
Institution: Northwestern University
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W3185801930