Exploratory data on the clinical efficacy of monoclonal antibodies against SARS-CoV-2 Omicron Variant of Concern

Abstract

BackgroundRecent in-vitro data have shown that the activity of monoclonal antibodies (mAbs) targeting SARS-CoV-2 varies according to the Variant of Concern (VOC). No studies have compared the clinical efficacy of different mAbs against Omicron VOC.MethodsThe MANTICO trial is a non-inferiority randomised controlled trial comparing the clinical efficacy of bamlanivimab/etesevimab, casirivimab/imdevimab, and sotrovimab in outpatients aged 50 or older with early COVID-19. 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 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.ResultsOverall, 319 patients were included. Among 141 patients infected with Delta, no disease progression was recorded and the time to symptom resolution did not differ significantly between treatment groups (Log-rank Chi-square 0.22, p 0.895). Among 170 patients infected with Omicron (80.6% BA.1, 19.4% BA.1.1), two disease progressions were recorded in the bamlanivimab/etesevimab group and the median time to symptom resolution was 5 days shorter in the sotrovimab group compared to bamlanivimab/etesevimab and casirivimab/imdevimab (HR 0.526 and HR 0.451, 95% CI 0.359 - 0.77 and 95% CI 0.303 - 0.669, p 0.001 and 0.0001, respectively).ConclusionsThese results confirm the in-vitro data of superiority of sotrovimab versus casirivimab/imdevimab and bamlanivimab/etesivamab in reducing the time to recovery in patients infected with Omicron BA.1 and BA.1.1, while no difference was detected in Delta infections. Casirivimab/imdevimab seems to maintain a role in preventing severe COVID-19 in the Omicron population. Adaptive clinical trials comparing mAbs by VOC should be pursued to promptly inform clinical recommendations.FundingThis 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 No 101016167.Clinical trial numberNCT05205759

Prescription of Anti-Spike Monoclonal Antibodies in COVID-19 Patients with Resistant SARS-CoV-2 Variants in Italy

“…Nowadays, resistance can be highly predicted on the basis of Spike mutational patterns observed in vitro ( Figure 6 ). Our hypothesis is substantiated by publications reporting usage in Italy of bamlanivimab against Gamma [ 41 ] despite notorious in vitro resistance [ 29 , 30 , 31 , 42 ], or the AIFA-sponsored MANTICO trial, authorized by the Ethical Committee of the National Institute of Infectious Diseases (INMI), which reported usage of casirivimab plus imdevimab against BA.1 [ 43 ].…”

Current Effective Therapeutics in Management of COVID-19

“…The primary limitation of baricitinib is renal dysfunction, and it is explicitly not recommended to be used in patients with eGFR < 15. The recommended dosing is based on renal clearance (4 mg daily for those with eGFR > 60, 2mg daily for those with eGFR 30-60, 1mg daily for eGFR [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30], and the treatment duration is up to 14 days or until hospital discharge. Patients most likely to benefit from baricitinib are those with high oxygen requirements, defined as BiPAP or HFNC, with an unclear though possible benefit in those patients requiring mechanical ventilation [75].…”

“…Both C+I and S are effective for use against the Delta variant, and are approved for use with Delta. Though Sotrovimab was shown to significantly benefit patients across all Omicron subgroups compared to C+I in a recent study [15], due to changes in the binding site of the Omicron variant, they are not recommended for use in Omicron and BA.2 variants [16][17][18].…”

COVID-19 and Adult Acute Leukemia: Our Knowledge in Progress

“…Other neutralizing spike antibodies showing promising results regarding the pre-exposition prophylaxis of COVID-19 are casirivimab and imdevimab, and the monoclonal antibody sotrovimab [ 74 ]. However, casirivimab, imdevimab, and sotrovimab showed less efficacy in vitro against the currently predominant SARS-CoV-2 variant Omicron and also appeared to be less effective in patients than the other neutralizing spike antibodies in reducing the time to recovery from the SARS-CoV-2 Omicron variant [ 75 , 76 ]. Therefore, the therapeutic impact of anti-spike-protein antibodies for the prevention and treatment of currently circulating SARS-CoV-2 variants (BA.2, BA.4, BA.5) remains unclear.…”

“…There is very limited data on the use of these antibodies in patients with AL. The choice of the antibody for treating COVID-19 should be based on national approval, local availability, and the current, local circulating SARS-CoV-2 variants, since not all antibodies could show efficacy against all SARS-CoV-2 variants [ 50 , 75 , 76 ]. Sotrovimab showed the highest efficacy against the Omicron variant amongst all SARS-CoV-2-moab and reduced the hospitalization and death rates in patients at risk for developing a severe COVID-19 course [ 84 , 85 ].…”