Tixagevimab-cilgavimab (AZD7442) for the treatment of patients hospitalized with COVID-19 (DisCoVeRy): A phase 3, randomized, double-blind, placebo-controlled trial

Résumé fourni par la source

Dear Editor, We read with great interest the recent article by Kamboj et al., in which they described the risk of developing moderate to severe Coronavirus Disease 2019 (COVID-19) in patients with hematological malignancies receiving tixagevimab-cilgavimab (T-C) during a period in which the dominant circulating variants of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) were resistant to T-C.1Kamboj M. Laracy J.C. Usiak S. Babady N.E. Yan J. Seo S.K. Outcomes of hematologic malignancy patients with SARS-CoV-2 breakthrough infections after tixagevimab-cilgavimab during community transmission of monoclonal antibody resistant variants.J Infect. 2023 Sep; 87: 282-285Abstract Full Text Full Text PDF PubMed Google Scholar The authors highlight the ongoing need to urgently address the mAb treatment gap, particularly for immunocompromised patients. The unmet need is further highlighted by the DisCoVeRy Phase 3, adaptive, multicenter European, randomized, double-blind, superiority trial that evaluated the efficacy and safety of intravenous T-C in SARS-CoV-2 antigenic positive patients (i.e. those with a high SARS-CoV-2 viral load) hospitalized with COVID-19 and followed-up to day 90. In the ambulatory setting, and while ancestral strains were circulating, the administration of intramuscular T-C to treat SARS-CoV-2 infections significantly reduced the risk of hospitalization and death in patients at risk for disease progression, compared to placebo.2Montgomery H. Hobbs F.D.R. Padilla F. Arbetter D. Templeton A. Seegobin S. et al.Efficacy and safety of intramuscular administration of tixagevimab–cilgavimab for early outpatient treatment of COVID-19 (TACKLE): a phase 3, randomised, double-blind, placebo-controlled trial.Lancet Respir Med. 2022; 10: 985-996Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar In the hospital setting, the double-blinded, placebo-controlled ACTIV-3-TICO trial evaluating T-C in 1417 patients with COVID-19, with >50% of participants infected with the Delta variant, demonstrated that treatment with T-C was associated with a 30% relative risk reduction in mortality (9% vs. 12%; hazard ratio [HR] 0.70 [95% confidence interval (CI) 0.50–0.97]; p = 0.032) through day 90.3Holland T.L. Ginde A.A. Paredes R. Murray T.A. Engen N. Grandits G. et al.Tixagevimab–cilgavimab for treatment of patients hospitalised with COVID-19: a randomised, doubleblind, phase 3 trial.Lancet Respir Med. 2022; 10: 972-984Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar The EU DisCoVeRy placebo-controlled trial (NCT04315948) began enrolling on April 28, 2021, after these trials were initiated (January 28, 2021, and February 10, 2021, respectively) and aimed to confirm efficacy and safety data in hospitalized COVID-19 patients during a later stage of the pandemic when the natural evolution of SARS-CoV-2 strains had led to the emergence of variants of concern (VOC), and mass vaccination campaigns had been ramped up worldwide.4Carabelli A.M. Peacock T.P. Thorne L.G. Harvey W.T. Hughes J. COVID-19 Genomics UK Consortium et al.SARS-CoV-2 variant biology: immune escape, transmission and fitness.Nat Rev Microbiol. 2023; ([cited November 3, 2023]; Available from: 〈https://www.nature.com/articles/s41579-022-00841-7〉)Crossref Scopus (326) Google Scholar In DisCoVeRy, participants were randomly assigned (1:1) to receive placebo or T-C in addition to standard of care (SoC), not including remdesivir. The primary outcome was the clinical status at day 15 measured by the WHO seven-point ordinal scale. Clinical, virological, immunological and safety endpoints were also assessed. In the context of in-vitro evidence showing loss of neutralization activity against emerging VOC,5Touret F. Giraud E. Bourret J. Donati F. Tran-Rajau J. Chiaravalli J. et al.Enhanced neutralization escape to therapeutic monoclonal antibodies by SARS-CoV-2 omicron sublineages.iScience. 2023; 26106413Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 6Takashita E. Yamayoshi S. Simon V. Van Bakel H. Sordillo E.M. Pekosz A. et al.Efficacy of antibodies and antiviral drugs against Omicron BA.2.12.1, BA.4, and BA.5 subvariants.N Engl J Med. 2022; 387: 468-470Crossref PubMed Scopus (187) Google Scholar enrollment slowed down until recruitment was stopped on July 1, 2022, before reaching the pre-determined targeted sample size of 1240 patients. As shown in Table 1, the antigen positive modified intention-to-treat population (mITT) included 173 participants randomized to T-C (n = 91) or placebo (n = 82), among whom 91.9% (159/173) needed supplementary oxygen, 19.6% (24/173) were immunocompromised, and 47.4% (82/173) were previously vaccinated against SARS-CoV-2 at inclusion. There was no difference in the distribution of the WHO ordinal scale at day 15 between the two groups (odds ratio (OR) 0.93, 95%CI [0.54–1.61]; p = 0.81) nor in any clinical, virological or safety secondary endpoints (Fig. 1). In the global mITT population (n = 226), neutralization antibody titers were significantly higher in the T-C recipients compared to placebo at day 3 (least-square mean differences (LSMD) 1.44, 95%CI [1.20–1.68]; p < 10−23) and day 8 (LSMD 0.91, 95%CI [0.64–1.18]; p < 10−8) and it was greatest for patients infected with a pre-Omicron variant, both at day 3 (LSMD 1.94, 95% CI [1.67–2.20], p < 10−25) and day 8 (LSMD 1.17, 95% CI [0.87–1.47], p < 10−9), with a significant interaction (p < 10−7 and p = 0.01 at days 3 and 8, respectively). A total of 178 adverse events (AEs), including 90 serious AEs (SAEs) were reported, of which 28 (31.1%) were considered related to the investigational medicinal product. In the T-C group, 51/123 (41.5%) patients had at least one AE, 30/123 (24.4%) had at least one grade 3 or 4 AE, and 28/123 (22.8%) had at least one SAE, against 45/103 (43.7%), 33 (32.0%), and 32 (31.1%) in the control group (p = 0.70, 0.18, and 0.13), respectively. Among 19 fatal SAEs, none were of cardiac origin. Complete results and all supporting documents are available on medRxiv (doi: 10.1101/2024.02.23.24302586).Table 1Baseline characteristics, clinical endpoints, and safety of participants in the antigen positive and global modified intention-to-treat populations, overall and according to the treatment group.Antigen positive (N = 173)Global (N = 226)OverallTixagevimab-cilgavimabPlaceboEffect measureOverallTixagevimab-cilgavimabPlaceboEffect measure(N = 173)(N = 91)(N = 82)(95% CI)(N = 226)(N = 123)(N = 103)(95% CI)Baseline characteristicsMedian age, years66.0 [55.0–79.0]65.0 [56.0–80.0]66.5 [55.0–78.0]66.0 [53.0–76.0]64.0 [53.0–76.0]68.0 [52.0–76.0]Sex male,117 (67.6%)56 (61.5%)61 (74.4%)155 (68.6%)78 (63.4%)77 (74.8%)Number of comorbidities*Denotes variables with missing data. The number of missing data is presented for the antigen positive/the global mITT for each variable, respectively. Data on smoking status (current) were missing in 3/3 participants; data on delay between first laboratory-confirmed SARS-CoV-2 infection and admission date at facility were missing in 1/1 participant; data on delay between first laboratory-confirmed SARS-CoV-2 infection and randomization were missing in 1/1 participant; data on serology test were missing on 2/5 participants; data on variant sequencing were missing in 35/71 participants; data on body weight were missing on 10/11 participants; data on NEWS2 score were missing on 16/20 participants. 038 (22.0%)17 (18.7%)21 (25.6%)52 (23.0%)28 (22.8%)24 (23.3%) 149 (28.3%)26 (28.6%)23 (28.0%)71 (31.4%)38 (30.9%)33 (32.0%) 243 (24.9%)23 (25.3%)20 (24.4%)50 (22.1%)27 (22.0%)23 (22.3%) 325 (14.5%)14 (15.4%)11 (13.4%)32 (14.2%)18 (14.6%)14 (13.6%) >318 (10.4%)11 (12.1%)7 (8.5%)21 (9.3%)12 (9.8%)9 (8.7%)Coexisting condition Chronic cardiac disease62 (35.8%)39 (42.9%)23 (28.0%)72 (31.9%)43 (35.0%)29 (28.2%) Obesity (BMI ≥ 30)46 (26.6%)27 (29.7%)19 (23.2%)63 (27.9%)38 (30.9%)25 (24.3%) Diabetes46 (26.6%)30 (33.0%)16 (19.5%)58 (25.7

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.