Tixagevimab–cilgavimab for treatment of patients hospitalised with COVID-19: a randomised, double-blind, phase 3 trial

Holland, Thomas L; Ginde, Adit A.; Paredes, Roger; Murray, Thomas A.; Engen, Nicole; Grandits, Greg; Vekstein, Andrew M.; Ivey, Noel; Mourad, Ahmad; Sandkovsky, Uriel; Gottlieb, Robert L; Berhe, Mezgebe; Jain, Mamta; Marines‐Price, Rubria; Agbor, Barbine Tchamba Agbor; Mateu, Lourdes; España-Cueto, Sergio; Lladós, Gemma; Mylonakis, Eleftherios; Rogers, Ralph; Shehadeh, Fadi; Filbin, Michael R.; Hibbert, Kathryn A.; Kim, Kami; Tran, Thanh; Morris, Peter E.; Cassity, Evan; Trautner, Barbara W.; Pandit, Lavannya; Knowlton, Kirk U.; Leither, Lindsay; Matthay, Michael A.; Rogers, Angela; Drake, Wonder; Jones, Beatrice; Poulakou, Garyfallia; Syrigos, Konstantinos; Fernández‐Cruz, Eduardo; Natale, Marisa Di; Almasri, Eyad; Balerdi-Sarasola, Leire; Bhagani, Sanjay; Boyle, Katherine L.; Casey, Jonathan D; Chen, Peter; Douin, David J.; Files, D. Clark; Günthard, Huldrych F.; Hite, R. Duncan; Hyzy, Robert C.; Khan, Akram; Kibirige, Moses; Kidega, Robert; Kimuli, Ivan; Kiweewa, Francis; Jensen, Jens‐Ulrik Stæhr; Leshnower, Bradley G.; Lutaakome, Joseph; Manian, Prasad; Menon, Vidya; Morales-Rull, J.L.; O’Mahony, D. Shane; Overcash, J. Scott; Ramachandruni, Srikant; Steingrub, Jay S.; Taha, Hassan S.; Waters, Michael R.; Young, Barnaby Edward; Phillips, Andrew; Murray, Daniel D.; Jensen, Tomas; Padilla, María L.; Sahner, David; Shaw-Saliba, Katy; Dewar, Robin; Teitelbaum, Marc; Natarajan, Ven; Rehman, Muhammad T; Pett, Sarah; Hudson, Fleur; Touloumi, Giota; Brown, Samuel M.; Self, Wesley H.; Chang, Christina C.; Sánchez, Adriana; Weintrob, Amy; Hatlen, Timothy; Grund, Birgit; Sharma, Shweta; Reilly, Cavan; Garbes, Pedro; Esser, Mark T.; Templeton, Alison; Babiker, Abdel; Davey, Victoria J.; Gelijns, Annetine C.; Higgs, Elizabeth; Kan, Virginia L.; Matthews, Gail; Thompson, B. Taylor; Neaton, James D.; Lane, H. Clifford; Lundgren, Jens D

doi:10.1016/s2213-2600(22)00215-6

Cited by 86 publications

(61 citation statements)

References 32 publications

(54 reference statements)

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“…The study population includes those who were randomly assigned in the TICO platform trial to receive 1 of 5 antiviral products (bamlanivimab [ 8 ], sotrovimab [ 2 ], amubarvimab–romlusevimab [ 2 ], tixagevimab–cilgavimab [ 23 ], and Molecular Partners MP0420 [ 24 ]) or matched placebo ( 22 ) and for whom a baseline assessment of the relevant biomarkers of interest was available.…”

Section: Methodsmentioning

confidence: 99%

The Association of Baseline Plasma SARS-CoV-2 Nucleocapsid Antigen Level and Outcomes in Patients Hospitalized With COVID-19

et al. 2022

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Section: Methodsmentioning

confidence: 99%

The Association of Baseline Plasma SARS-CoV-2 Nucleocapsid Antigen Level and Outcomes in Patients Hospitalized With COVID-19

et al. 2022

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“…Full results from the phase 1 trial will be published in due course. Overall, the assays presented were utilized in support of bioanalysis of samples from preclinical and multiple clinical studies. − …”

Section: Resultsmentioning

confidence: 99%

Multiplex Hybrid Antigen-Capture LC-MRM Quantification in Sera and Nasal Lining Fluid of AZD7442, a SARS-CoV-2-Targeting Antibody Combination

Huang

Bouquet

et al. 2022

Anal. Chem.

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AZD7442 (tixagevimab [AZD8895]/cilgavimab [AZD1061]) is a monoclonal antibody (mAb) combination in development for the prevention and treatment of coronavirus disease 2019. Traditionally, bioanalysis of mAbs is performed using ligand binding assays (LBAs), which offer sensitivity, robustness, and ease of implementation. However, LBAs frequently require generation of critical reagents that typically take several months. Instead, we developed a highly sensitive (5 ng/mL limit of quantification) method using a hybrid LBA-liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) approach for quantification of the two codosed antibodies in serum and nasal lining fluid (NLF), a rare matrix. The method was optimized by careful selection of multiple reaction monitoring, capture reagents, magnetic beads, chromatographic conditions, evaluations of selectivity, and matrix effect. The final assay used viral spike protein receptor-binding domain as capture reagent and signature proteotypic peptides from the complementarity-determining region of each mAb for detection. In contrast to other methods of similar/superior sensitivity, our approach did not require multidimensional separations and can be operated in an analytical flow regime, ensuring high throughput and robustness required for clinical analysis at scale. The sensitivity of this method significantly exceeds typical sensitivity of ∼100 ng/mL for analytical flow 1D LBA-LC-MS/MS methods for large macromolecules, such as antibodies. Furthermore, infection and vaccination status did not impact method performance, ensuring method robustness and applicability to a broad patient population. This report demonstrated the general applicability of the hybrid LBA-LC-MS/MS approach to platform quantification of antibodies with high sensitivity and reproducibility, with specialized extension to matrices of increasing interest, such as NLF.

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“…It is noteworthy that neither the primary outcome of time to sustained recovery nor pulmonary function at day 5 (odds ratio 1·08 (95% CI 0·89–1·30) was improved with tixagevimab–cilgavimab. 8 However, tixagevimab–cilgavimab passed the early futility analysis and was permitted to continue enrolment. Therefore, it is unknown whether these failed monoclonal antibodies would have shown a mortality benefit in a larger trial despite no effect on the ordinal outcome scales, as was the case with tixagevimab–cilgavimab.…”

mentioning

confidence: 99%

“… 1 , 2 , 3 Conversely, results of randomised trials in patients who are hospitalised are mixed. 4 , 5 , 6 , 7 , 8 In The Lancet Respiratory Medicine , Thomas L Holland and colleagues present results of the ACTIV-3 trial comparing intravenous tixagevimab−cilgavimab with placebo for patients hospitalised with COVID-19. 8 Although tixagevimab−cilgavimab did not improve the primary outcome of time to sustained recovery (rate ratio [RR] 1·08 [95% CI 0·97–1·20]; p=0·21), it was associated with improved 28-day (6% vs 9%; p=0·02) and 90-day (9% vs 12%; p=0·03) mortality.…”

mentioning

confidence: 99%

“…Indeed, in ACTIV-3, 28-day mortality was identical (13%) in the tixagevimab–cilgavimab and placebo groups in the subset of patients who were vaccinated. 8 With up to five vaccine doses now recommended, and the decreased risk of death in those vaccinated, 10 the efficacy of tixagevimab–cilgavimab in these patients is unclear. Furthermore, nearly all unvaccinated patients have now been previously infected with SARS-CoV-2.…”

mentioning

confidence: 99%

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Monoclonals for patients hospitalised with COVID-19

Pogue¹,

McCreary²

2022

The Lancet Respiratory Medicine

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Tixagevimab–cilgavimab for treatment of patients hospitalised with COVID-19: a randomised, double-blind, phase 3 trial

Cited by 86 publications

References 32 publications

The Association of Baseline Plasma SARS-CoV-2 Nucleocapsid Antigen Level and Outcomes in Patients Hospitalized With COVID-19

The Association of Baseline Plasma SARS-CoV-2 Nucleocapsid Antigen Level and Outcomes in Patients Hospitalized With COVID-19

Multiplex Hybrid Antigen-Capture LC-MRM Quantification in Sera and Nasal Lining Fluid of AZD7442, a SARS-CoV-2-Targeting Antibody Combination

Monoclonals for patients hospitalised with COVID-19

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