Exploratory data on the clinical efficacy of monoclonal antibodies against SARS-CoV-2 Omicron variant of concern

  1. Fulvia Mazzaferri
  2. Massimo Mirandola
  3. Alessia Savoldi
  4. Pasquale De Nardo
  5. Matteo Morra
  6. Maela Tebon
  7. Maddalena Armellini
  8. Giulia De Luca
  9. Lucrezia Calandrino
  10. Lolita Sasset
  11. Denise D'Elia
  12. Emanuela Sozio
  13. Elisa Danese
  14. Davide Gibellini
  15. Isabella Monne
  16. Giovanna Scroccaro
  17. Nicola Magrini
  18. Annamaria Cattelan
  19. Carlo Tascini
  20. MANTICO Working Group
  21. Evelina Tacconelli

  • Curated by eLife

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    Evaluation Summary:

    This paper will be of broad interest to clinicians and scientists in the area, providing clinical trial data on how the efficacy of monoclonal antibodies targeting SARS-CoV-2 varies according to the variant of concern. The clinical outcome data were consistent with previously reported in vitro data, which are being used to inform the clinical use of monoclonal antibodies. However, as the trial was stopped early, conclusions regarding the efficacy and safety of the individual monoclonal antibodies are limited.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)

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Abstract

Recent in-vitro data have shown that the activity of monoclonal antibodies (mAbs) targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) varies according to the variant of concern (VOC). No studies have compared the clinical efficacy of different mAbs against Omicron VOC.

Methods:

The MANTICO trial is a non-inferiority randomised controlled trial comparing the clinical efficacy of early treatments with bamlanivimab/etesevimab, casirivimab/imdevimab, and sotrovimab in outpatients aged 50 or older with mild-to-moderate SARS-CoV-2 infection. As the patient enrolment was interrupted for possible futility after the onset of the Omicron wave, the analysis was performed according to the SARS-CoV-2 VOC. The primary outcome was coronavirus disease 2019 (COVID-19) progression (hospitalisation, need of supplemental oxygen therapy, or death through day 14). Secondary outcomes included the time to symptom resolution, assessed using the product-limit method. Kaplan-Meier estimator and Cox proportional hazard model were used to assess the association with predictors. Log rank test was used to compare survival functions.

Results:

Overall, 319 patients were included. Among 141 patients infected with Delta, no COVID-19 progression was recorded, and the time to symptom resolution did not differ significantly between treatment groups (Log-rank Chi-square 0.22, p 0.90). Among 170 patients infected with Omicron (80.6% BA.1 and 19.4% BA.1.1), two COVID-19 progressions were recorded, both in the bamlanivimab/etesevimab group, and the median time to symptom resolution was 5 days shorter in the sotrovimab group compared with the bamlanivimab/etesevimab and casirivimab/imdevimab groups (HR 0.53 and HR 0.45, 95% CI 0.36–0.77 and 95% CI 0.30–0.67, p<0.01).

Conclusions:

Our data suggest that, among adult outpatients with mild-to-moderate SARS-CoV-2 infection due to Omicron BA.1 and BA.1.1, early treatment with sotrovimab reduces the time to recovery compared with casirivimab/imdevimab and bamlanivimab/etesevimab. In the same population, early treatment with casirivimab/imdevimab may maintain a role in preventing COVID-19 progression. The generalisability of trial results is substantially limited by the early discontinuation of the trial and firm conclusions cannot be drawn.

Funding:

This trial was funded by the Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA). The VOC identification was funded by the ORCHESTRA (Connecting European Cohorts to Increase Common and Effective Response to SARS-CoV-2 Pandemic) project, which has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement number 101016167.

Clinical trial number:

NCT05205759.

Article activity feed

  1. Version published to 10.7554/elife.79639 on eLife
  2. eLife

    Evaluation Summary:

    This paper will be of broad interest to clinicians and scientists in the area, providing clinical trial data on how the efficacy of monoclonal antibodies targeting SARS-CoV-2 varies according to the variant of concern. The clinical outcome data were consistent with previously reported in vitro data, which are being used to inform the clinical use of monoclonal antibodies. However, as the trial was stopped early, conclusions regarding the efficacy and safety of the individual monoclonal antibodies are limited.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)

  3. eLife

    Reviewer #1 (Public Review):

    This is a randomized controlled trial to assess the impact on the COVID-19 progression (hospitalization, oxygen supplementation need, and/or death within 14 days) of 3 different mAbs. As only one of the assessed mAbs was shown to be active in vitro against the Omicron variant, which emerged after the study onset, the trial was interrupted for potential futility. The authors compared the activity of three mAbs in patients infected with Delta and in those with Omicron variant. Symptoms duration was shorter in patients treated with sotrovimab than in those treated with the other mAbs, mainly among Omicron infected patients. No disease progression was observed in the Delta group, while two patients infected with omicron and treated with bamlanivimab/etesevimab presented progression.

    The strength of this study is that it provides clinical data about the efficacy of different mAbs on COVID-19 progression against the Omicron variant assessed by a pragmatic RCT.

    The limitation is the reduced sample size.

    The results are useful in confirming the usefulness of Sotrovimab in the management of patients with Omicron BA 1 and BA 1.1. They cannot be applied to other Omicron sub-lineages.

    Considering the availability of antiviral agents for early use in patients with asymptomatic or mild infection but with risk factors for COVID-19 progression and the longer duration of symptoms observed for casirivimab/imdevimab compared with sotrovimab, the conclusion about the potential role of this mAb against Omicron seems inappropriate.

  4. eLife

    Reviewer #2 (Public Review):

    The MANTICO trial sought to generate real-world evidence comparing three widely used anti-SARS-CoV-2 monoclonal antibodies (bamlanivimab/etesevimab, casirivimab/imdevimab, and sotrovimab) all of which were approved for treatment at the time the study was designed and commenced recruitment. These are antibody medications that bind to the SARS-CoV-2 virus and prevent it from entering cells. Before being licensed for use, these antibodies had all been studied against placebo and were shown to be effective therapies in specific patient groups. However, data were lacking on the relative effects of the three treatments; Simbeni et all sought to provide this important information. Conducting a comparative effectiveness study like the MANTICO trial efficiently during a pandemic is challenging and Simbeni and colleagues should be congratulated for their efforts to rapidly generate useful data for clinicians and patients. The trial was well designed, with randomised treatment assignment and single blinding (the clinicians were aware of which of the three monoclonal antibodies a participant had been assigned, and they prescribed this agent, but the participant gave informed consent to receive any of the three antibodies and were not aware which one they were administered).

    The MANTICO trial encountered challenges relatively unique to pandemic trials and especially pronounced in trials studying neutralising monoclonal antibodies, which are often only effective, at least in vitro (in laboratory tests), against certain SARS-CoV-2. At the beginning of the trial, all three study medications were recommended for the treatment of COVID-19. However, in vitro evidence from tests of viral variants growing in cells in a laboratory (rather than clinical trial evidence) indicated that two of the three monoclonal antibodies in the MANTICO study - bamlanivimab/etesevimab and casirivimab/imdevimab - were far less effective at neutralising omicron variants of SARS-CoV-2 than previous variants, such as delta. This resulted in treatment guidelines withdrawing their recommendation to use these two agents for the treatment of COVID-19. Consequently, the MANTICO trial closed to enrolment after recruiting only 319 of the planned 1260 participants (~25% of planned enrolment). While it may have been scientifically rational to seek to continue to generate randomised clinical trial data comparing these three treatments, given the limitations of extrapolating from in vitro data to human patients, that would have been difficult when one of the three agents (sotrovimab) retained much of its neutralising activity against omicron BA.1 in vitro. This meant that sotrovimab remained the standard of care for some COVID-19 patients, recommended in guidelines where BA.1 predominated, whereas two of the three agents had guidelines recommending against their use in this setting. Continuing to generate RCT evidence would have required a re-design of the trial, further ethical review, etc. Reasonably, MANTICO closed enrolment but continued to collect follow-up data on its 319 participants.

    In this paper, Simbeni et al present data from the 319 participants who enrolled in the MANTICO study, focusing on the subset of these 319 participants for whom variant of concern information was available (n=311). They contrast clinical outcomes with the three medications in the two cohorts - delta (n=141) and omicron (n=170). Strengths of this approach include the study period covering the time where omicron infections overtook delta, leaving two similarly sized cohorts, a high proportion of patients with viral genomic sequencing data, and the randomisation of treatments within each of these delta and omicron cohorts. The major limitation is the lack of power, resulting from the early termination of the study and the resultant small sample size. This, coupled with the low event rate means the study is significantly underpowered to detect a difference in the primary outcome selected by the investigators (COVID-19 disease progression), which occurred in 0/141 (0%) of participants with delta and in 2/171 (1.2%) of participants with omicron. These data are not well-presented to readers, as the manuscript stands. The occurrence of the primary outcome variable (and secondary outcome variables) in the different treatment groups is not presented in table format. Figures 1 and 2 both relate to the secondary outcome of time to symptom resolution, rather than the study's primary outcome. Therefore, the way the data are presented is an additional limitation, affecting how readily those reading the manuscript can understand the trial results.

    The authors note that the only two cases of COVID-19 disease progression in the study occurred in the omicron cohort and in participants allocated to bamlanivimab/etesevimab, rather than casirivimab/imdevimab or sotrovimab. They go on to conclude that "casirivimab/imdevimab seems to maintain a role in preventing severe COVID-19 in the Omicron population"; this is not a conclusion that can be substantiated by the data presented. It is of interest that there were no cases of disease progression in those allocated to sotrovimab (the agent that retained more in vitro activity against omicron and is still a recommended treatment option for some BA.1 patients in therapeutic guidelines) or casirivimab/imdevimab (no longer recommended in therapeutic guidelines, with markedly reduced activity against omicron) and that the instances of disease progression occurred in the bamlanivimab/etesevimab group (an agent with essentially no activity against omicron in vitro). However, with such a low event rate (two cases of COVID-19 disease progression in the entire trial), such a finding could easily be due to chance, can only be hypothesis-generating, and does not warrant the conclusion "Casirivimab/imdevimab seems to maintain a role in preventing severe COVID-10 in the Omicron population". Further, the secondary analysis of time to symptom resolution suggests more caution is required before drawing any conclusions about the clinical effectiveness of casirivimab/imdevimab in an omicron context. The time to symptom resolution was 5 days shorter in the sotrovimab group compared to bamlanivimab/etesevimab (HR 0.526, 95%, CI 0.359 - 0.77) and casirivimab/imdevimab (HR 0.451, 95% CI 0.303 - 0.669). Given this is an outcome derived from self-reported symptoms, the blinding of participants to which treatment they received is important and is a strength of the study.

    The authors were not able to compare the clinical effectiveness of these three agents because of factors outside of their control, something which should not curb efforts to generate further data in a fast-moving pandemic. They have sought to advance our understanding of the utility of monoclonal antibody treatments by providing variant-specific analyses of the effect of these agents from a well-designed randomised clinical trial. However, the presented data, from what has ended up being an underpowered analysis of a trial stopped early for operational reasons, requires careful interpretation. This is particularly true when considering the primary outcome variable - COVID-19 disease progression. The trial enrolled 25% of the planned sample size but also noted a lower event rate (~0.6%) than that which was used to inform the sample size considerations (outlined on the clinicaltrials.gov register at https://clinicaltrials.gov/ct2/show/NCT05205759). And this low event rate has important implications, in terms of the size of a randomised clinical trial necessary to generate robust data here, and the likely real-world number needed to treat with these an agent such as casirivimab/imdevimab).

  5. eLife

    Reviewer #3 (Public Review):

    The MANTICO trial was a 319-patient randomized comparative effectiveness trial of three monoclonal antibodies for COVID-19, during a period of time when the Delta variant was starting to become replaced by the Omicron variant. Due to this unique time period and patient-level variant typing, the trial was able to compare the three antibodies, stratified by variant. Overall, their clinical findings were consistent with in vitro data regarding these antibodies versus variants; this result is of interest as authorization and treatment decisions are being made based on in vitro data, which do not always prove consistent with clinical outcomes.

    The major strength is the randomized design, which allows strong causal inference. The major weakness is the limited sample size, due to 2 of the antibodies becoming unavailable, thus forcing the authors to stop the trial early. In addition, as fortunately almost all patients did well, the primary outcome of hospitalization, need for oxygen, or death was non-informative, as were most secondary outcomes, and the authors hinged their conclusions on 1 of multiple secondary outcomes (thus raising the possibility of false discovery due to multiple comparisons).

    Nonetheless, the authors largely achieved their aims, and their results generally support their conclusions.

    The likely impact of the work is that it reassures the public that authorization and treatment decisions being made on in vitro data (test tube experiments) are likely reliable, as this study found clinical outcomes consistent with in vitro data. Thus, although the current variants are different from the variants treated in this trial, their overall results are compelling.

  6. ScreenIT

    SciScore for 10.1101/2022.05.06.22274613: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsIACUC: The trial was conducted in accordance with the principles of the Declaration of Helsinki, the international ethical guidelines of the Council for International Organizations of Medical Sciences, the International Council for Harmonisation Good Clinical Practice guidelines, and applicable laws and regulations.
    Consent: All patients or their legally authorized representatives provided written informed consent.
    Sex as a biological variablenot detected.
    RandomizationTrial design: The trial was designed as a pragmatic, randomised, single-blind, non-inferiority, parallel group, multi-centre, controlled trial.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    According to the to manufacturer’s instructions, Binding Antibody Units (BAU)/mL ≥ 33.8 were considered positive for anti-trimeric spike protein specific IgG antibodies.
    anti-trimeric spike protein specific IgG
    suggested: None
    Software and Algorithms
    SentencesResources
    The allocated drug was revealed to the investigator using an online randomisation module within the REDCap data management system [13].
    REDCap
    suggested: (REDCap, RRID:SCR_003445)
    : StataCorp LP).
    StataCorp
    suggested: (Stata, RRID:SCR_012763)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT05205759TerminatedNon-inferiority Trial on Monoclonal Antibodies in COVID-19

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • No funding statement was detected.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  7. Version published to 10.1101/2022.05.06.22274613v1 on medRxiv