SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19

Nina Kreuzberger, Caroline Hirsch, Khai Li Chai, Eve Tomlinson, Zahra Khosravi, Maria Popp, Miriam Neidhardt, Vanessa Piechotta, Susanne Salomon, Sarah J Valk, Ina Monsef, Christoph Schmaderer, Erica M Wood, Cynthia So-Osman, David J Roberts, Zoe McQuilten, Lise J Estcourt, Nicole Skoetz, Nina Kreuzberger, Caroline Hirsch, Khai Li Chai, Eve Tomlinson, Zahra Khosravi, Maria Popp, Miriam Neidhardt, Vanessa Piechotta, Susanne Salomon, Sarah J Valk, Ina Monsef, Christoph Schmaderer, Erica M Wood, Cynthia So-Osman, David J Roberts, Zoe McQuilten, Lise J Estcourt, Nicole Skoetz

Abstract

Background: Monoclonal antibodies (mAbs) are laboratory-produced molecules derived from the B cells of an infected host. They are being investigated as a potential therapy for coronavirus disease 2019 (COVID-19).

Objectives: To assess the effectiveness and safety of SARS-CoV-2-neutralising mAbs for treating patients with COVID-19, compared to an active comparator, placebo, or no intervention. To maintain the currency of the evidence, we will use a living systematic review approach. A secondary objective is to track newly developed SARS-CoV-2-targeting mAbs from first tests in humans onwards. SEARCH METHODS: We searched MEDLINE, Embase, the Cochrane COVID-19 Study Register, and three other databases on 17 June 2021. We also checked references, searched citations, and contacted study authors to identify additional studies. Between submission and publication, we conducted a shortened randomised controlled trial (RCT)-only search on 30 July 2021.

Selection criteria: We included studies that evaluated SARS-CoV-2-neutralising mAbs, alone or combined, compared to an active comparator, placebo, or no intervention, to treat people with COVID-19. We excluded studies on prophylactic use of SARS-CoV-2-neutralising mAbs.

Data collection and analysis: Two authors independently assessed search results, extracted data, and assessed risk of bias using the Cochrane risk of bias tool (RoB2). Prioritised outcomes were all-cause mortality by days 30 and 60, clinical progression, quality of life, admission to hospital, adverse events (AEs), and serious adverse events (SAEs). We rated the certainty of evidence using GRADE.

Main results: We identified six RCTs that provided results from 17,495 participants with planned completion dates between July 2021 and December 2031. Target sample sizes varied from 1020 to 10,000 participants. Average age was 42 to 53 years across four studies of non-hospitalised participants, and 61 years in two studies of hospitalised participants. Non-hospitalised individuals with COVID-19 Four studies evaluated single agents bamlanivimab (N = 465), sotrovimab (N = 868), regdanvimab (N = 307), and combinations of bamlanivimab/etesevimab (N = 1035), and casirivimab/imdevimab (N = 799). We did not identify data for mortality at 60 days or quality of life. Our certainty of the evidence is low for all outcomes due to too few events (very serious imprecision). Bamlanivimab compared to placebo No deaths occurred in the study by day 29. There were nine people admitted to hospital by day 29 out of 156 in the placebo group compared with one out of 101 in the group treated with 0.7 g bamlanivimab (risk ratio (RR) 0.17, 95% confidence interval (CI) 0.02 to 1.33), 2 from 107 in the group treated with 2.8 g (RR 0.32, 95% CI 0.07 to 1.47) and 2 from 101 in the group treated with 7.0 g (RR 0.34, 95% CI 0.08 to 1.56). Treatment with 0.7 g, 2.8 g and 7.0 g bamlanivimab may have similar rates of AEs as placebo (RR 0.99, 95% CI 0.66 to 1.50; RR 0.90, 95% CI 0.59 to 1.38; RR 0.81, 95% CI 0.52 to 1.27). The effect on SAEs is uncertain. Clinical progression/improvement of symptoms or development of severe symptoms were not reported. Bamlanivimab/etesevimab compared to placebo There were 10 deaths in the placebo group and none in bamlanivimab/etesevimab group by day 30 (RR 0.05, 95% CI 0.00 to 0.81). Bamlanivimab/etesevimab may decrease hospital admission by day 29 (RR 0.30, 95% CI 0.16 to 0.59), may result in a slight increase in any grade AEs (RR 1.15, 95% CI 0.83 to 1.59) and may increase SAEs (RR 1.40, 95% CI 0.45 to 4.37). Clinical progression/improvement of symptoms or development of severe symptoms were not reported. Casirivimab/imdevimab compared to placebo Casirivimab/imdevimab may reduce hospital admissions or death (2.4 g: RR 0.43, 95% CI 0.08 to 2.19; 8.0 g: RR 0.21, 95% CI 0.02 to 1.79). We are uncertain of the effect on grades 3-4 AEs (2.4 g: RR 0.76, 95% CI 0.17 to 3.37; 8.0 g: RR 0.50, 95% CI 0.09 to 2.73) and SAEs (2.4 g: RR 0.68, 95% CI 0.19 to 2.37; 8.0 g: RR 0.34, 95% CI 0.07 to 1.65). Mortality by day 30 and clinical progression/improvement of symptoms or development of severe symptoms were not reported. Sotrovimab compared to placebo We are uncertain whether sotrovimab has an effect on mortality (RR 0.33, 95% CI 0.01 to 8.18) and invasive mechanical ventilation (IMV) requirement or death (RR 0.14, 95% CI 0.01 to 2.76). Treatment with sotrovimab may reduce the number of participants with oxygen requirement (RR 0.11, 95 % CI 0.02 to 0.45), hospital admission or death by day 30 (RR 0.14, 95% CI 0.04 to 0.48), grades 3-4 AEs (RR 0.26, 95% CI 0.12 to 0.60), SAEs (RR 0.27, 95% CI 0.12 to 0.63) and may have little or no effect on any grade AEs (RR 0.87, 95% CI 0.66 to 1.16). Regdanvimab compared to placebo Treatment with either dose (40 or 80 mg/kg) compared with placebo may decrease hospital admissions or death (RR 0.45, 95% CI 0.14 to 1.42; RR 0.56, 95% CI 0.19 to 1.60, 206 participants), but may increase grades 3-4 AEs (RR 2.62, 95% CI 0.52 to 13.12; RR 2.00, 95% CI 0.37 to 10.70). 80 mg/kg may reduce any grade AEs (RR 0.79, 95% CI 0.52 to 1.22) but 40 mg/kg may have little to no effect (RR 0.96, 95% CI 0.64 to 1.43). There were too few events to allow meaningful judgment for the outcomes mortality by 30 days, IMV requirement, and SAEs. Hospitalised individuals with COVID-19 Two studies evaluating bamlanivimab as a single agent (N = 314) and casirivimab/imdevimab as a combination therapy (N = 9785) were included. Bamlanivimab compared to placebo We are uncertain whether bamlanivimab has an effect on mortality by day 30 (RR 1.39, 95% CI 0.40 to 4.83) and SAEs by day 28 (RR 0.93, 95% CI 0.27 to 3.14). Bamlanivimab may have little to no effect on time to hospital discharge (HR 0.97, 95% CI 0.78 to 1.20) and mortality by day 90 (HR 1.09, 95% CI 0.49 to 2.43). The effect of bamlanivimab on the development of severe symptoms at day 5 (RR 1.17, 95% CI 0.75 to 1.85) is uncertain. Bamlanivimab may increase grades 3-4 AEs at day 28 (RR 1.27, 95% CI 0.81 to 1.98). We assessed the evidence as low certainty for all outcomes due to serious imprecision, and very low certainty for severe symptoms because of additional concerns about indirectness. Casirivimab/imdevimab with usual care compared to usual care alone Treatment with casirivimab/imdevimab compared to usual care probably has little or no effect on mortality by day 30 (RR 0.94, 95% CI 0.87 to 1.02), IMV requirement or death (RR 0.96, 95% CI 0.90 to 1.04), nor alive at hospital discharge by day 30 (RR 1.01, 95% CI 0.98 to 1.04). We assessed the evidence as moderate certainty due to study limitations (lack of blinding). AEs and SAEs were not reported. AUTHORS' CONCLUSIONS: The evidence for each comparison is based on single studies. None of these measured quality of life. Our certainty in the evidence for all non-hospitalised individuals is low, and for hospitalised individuals is very low to moderate. We consider the current evidence insufficient to draw meaningful conclusions regarding treatment with SARS-CoV-2-neutralising mAbs. Further studies and long-term data from the existing studies are needed to confirm or refute these initial findings, and to understand how the emergence of SARS-CoV-2 variants may impact the effectiveness of SARS-CoV-2-neutralising mAbs. Publication of the 36 ongoing studies may resolve uncertainties about the effectiveness and safety of SARS-CoV-2-neutralising mAbs for the treatment of COVID-19 and possible subgroup differences.

Trial registration: ClinicalTrials.gov NCT04501978 NCT04427501 NCT04545060 NCT04602000 NCT04381936 NCT04425629 NCT04505774 NCT04280705 NCT04401579 NCT04492475 NCT04602260 NCT04356495 NCT04561063 NCT04333732 NCT04534725 NCT04371367 NCT04382651 NCT04275245 NCT04341116 NCT04354428 NCT04369469 NCT04370262 NCT04415073 NCT04453384 NCT04454398 NCT04469179 NCT04494724 NCT04494984 NCT04497987 NCT04498273 NCT04516564 NCT04569786 NCT04574869 NCT04586153 NCT04629703 NCT04766671 NCT04859517 NCT04894474 NCT04333420 NCT04621149 NCT04625972 NCT04429529 NCT04441918 NCT04441931 NCT04479631 NCT04479644 NCT04483375 NCT04507256 NCT04519437 NCT04525079 NCT04532294 NCT04533048 NCT04537910 NCT04561076 NCT04567810 NCT04590430 NCT04592549 NCT04603651 NCT04617535 NCT04656691 NCT04691180 NCT04700163 NCT04701658 NCT04896541 NCT04932850 NCT04351724 NCT04593940 NCT04640168 NCT04583956 NCT04583969 NCT04355143 NCT04662086 NCT04324047 NCT04328012 NCT04473053 NCT04891133 NCT04488081 NCT04590586 NCT04452318 NCT04703608 NCT04386070 NCT02735707 NCT04826588 NCT04393246 NCT04390464 NCT04445467 NCT04518410 NCT04746183 NCT04315948 NCT04411628 NCT04426695 NCT04551898 NCT04584697 NCT04593641 NCT04627584 NCT04631666 NCT04631705 NCT04634409 NCT04644120 NCT04644185 NCT04649515 NCT04666441 NCT04674566 NCT04683328 NCT04709328 NCT04723394 NCT04734860 NCT04748588 NCT04770467 NCT04771351 NCT04779879 NCT04780321 NCT04787211 NCT04796402 NCT04805671 NCT04822701 NCT04900428 NCT04913675 NCT04952805 NCT04790786.

Conflict of interest statement

NK: is funded by the Federal Ministry of Education and Research, Germany (NaFoUniMedCovid19, funding number: 01KX2021; part of the project 'COVIM', which was paid to the institution).

CH: none known

KLC: none known

ET: none known

ZK: none known

MP: none known

MN: is funded by the Federal Ministry of Education and Research, Germany (NaFoUniMedCovid19, funding number: 01KX2021; part of the project 'COVIM', which was paid to the institution).

VP: none known

SS: is funded by the Federal Ministry of Education and Research, Germany (NaFoUniMedCovid19, funding number: 01KX2021; part of the project 'COVIM' which was paid to the institution).

SJV: receives a PhD scholarship from the not‐for‐profit Sanquin blood bank.

IM: none known

CS: none known

EMW: none known

CS‐O: has declared to be employed by the not‐for‐profit Sanquin blood bank.

DJR: is a consultant haematologist for NHS Blood and Transplant.

ZM: is a haematologist at Monash University.

LJE: is a consultant haematologist for NHS Blood and Transplant.

NS: none known