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

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%)37 (30.1%)21 (20.4%) Current smoker13 (48.1%)6 (42.9%)7 (53.8%)15 (48.4%)7 (46.7%)8 (50.0%) Chronic pulmonary disease (including asthma)43 (24.9%)22 (24.2%)21 (25.6%)53 (23.5%)27 (22.0%)26 (25.2%) Active cancer (including hematological malignancy)23 (13.3%)9 (9.9%)14 (17.1%)30 (13.3%)12 (9.8%)18 (17.5%)Median days from symptoms onset and random assignment*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., +Only conditions with a relative frequency greater than 10% are displayed in the table.*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.7.0 [5.0–9.0]7.0 [6.0–9.0]7.0 [5.0–9.0]7.0 [6.0–9.0]8.0 [6.0–9.0]7.0 [5.0–9.0]NEWS2 score*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.7.0 [5.0–9.0]7.0 [5.0–8.0]7.0 [5.0–9.0]7.0 [5.0–9.0]7.0 [5.0–8.0]6.0 [5.0–9.0]Clinical status 3. Hospitalized, not requiring supplemental oxygen7 (4.0%)5 (5.5%)2 (2.4%)9 (4.0%)6 (4.9%)3 (2.9%) 4. Hospitalized, requiring supplemental oxygen141 (81.5%)71 (78.0%)70 (85.4%)179 (79.2%)93 (75.6%)86 (83.5%) 5. Hospitalized, on non-invasive ventilation or high flow oxygen devices25 (14.5%)15 (16.5%)10 (12.2%)38 (16.8%)24 (19.5%)14 (13.6%)Randomization site Intensive care unit21 (12.1%)15 (16.5%)6 (7.3%)32 (14.2%)21 (17.1%)11 (10.7%) Conventional unit152 (87.9%)76 (83.5%)76 (92.7%)194 (85.8%)102 (82.9%)92 (89.3%)Vaccination initiation (partly or fully)82 (47.4%)43 (47.3%)39 (47.6%)102 (45.1%)56 (45.5%)46 (44.7%)Serology*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. Negative (anti-N antibodies -and anti-S RBD antibodies -)69 (40.4%)40 (44.4%)29 (35.8%)76 (34.4%)44 (36.4%)32 (32.0%) Positive (anti-N antibodies + or anti-S RBD antibodies +)102 (59.6%)50 (55.6%)52 (64.2%)145 (65.6%)77 (63.6%)68 (68.0%)Variant Omicron on day 1 (imputed)*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. Pre-Omicron99 (57.2%)52 (57.1%)47 (57.3%)133 (58.8%)70 (56.9%)63 (61.2%) Omicron BA144 (25.4%)25 (27.5%)19 (23.2%)53 (23.5%)32 (26.0%)21 (20.4%) Omicron BA2/520 (11.6%)10 (11.0%)10 (12.2%)22 (9.7%)11 (8.9%)11 (10.7%) Unknown10 (5.8%)4 (4.4%)6 (7.3%)18 (8.0%)10 (8.1%)8 (7.8%)Median normalized viral load in nasopharyngeal swabs at baseline, log10 copies per 10,000 cells‡Undetectable viral load values (i.e. values < 1 log10 copies/10 000 cells) were imputed to 0.7 log10 copies/10 000 cells.4.4 [3.3–5.4]4.4 [3.4–5.3]4.4 [3.3–5.6]4.0 [2.5–5.2]3.9 [2.4–5.1]4.1 [2.7–5.3]Clinical endpoints7-point ordinal scale at day 15 1. Not hospitalized, no limitations on activities35 (20.2%)15 (16.5%)20 (24.4%)OR = 0.93 (0.54–1.61) [p = 0.81]48 (21.2%)20 (16.3%)28 (27.2%)OR = 0.85 (0.52–1.37) [p = 0.50] 2. Not hospitalized, limitation on activities77 (44.5%)45 (49.5%)32 (39.0%)104 (46.0%)63 (51.2%)41 (39.8%) 3. Hospitalized, not requiring supplemental oxygen18 (10.4%)9 (9.9%)9 (11.0%)24 (10.6%)14 (11.4%)10 (9.7%) 4. Hospitalized, requiring supplemental oxygen9 (5.2%)7 (7.7%)2 (2.4%)13 (5.8%)10 (8.1%)3 (2.9%) 5. Hospitalized, on non-invasive ventilation or high flow oxygen devices6 (3.5%)2 (2.2%)4 (4.9%)7 (3.1%)2 (1.6%)5 (4.9%) 6. Hospitalized, on invasive mechanical ventilation or ECMO11 (6.4%)5 (5.5%)6 (7.3%)12 (5.3%)6 (4.9%)6 (5.8%) 7. Death17 (9.8%)8 (8.8%)9 (11.0%)18 (8.0%)8 (6.5%)10 (9.7%)Time to sustained recovery through day 90 (days)22.0 [19.0–27.0]22.0 [19.0–27.5]21.0 [18.0–27.0]HR = 0.98 (0.71–1.36) [p = 0.92]21.0 [18.0–27.0]22.0 [19.0–27.5]21.0 [18.0–27.0]HR = 1.01 (0.77–1.34) [p = 0.93]Days to hospital discharge before day 908.0 [6.0–13.0]8.0 [6.0–11.0]9.0 [5.0–13.0]HR = 1.06 (0.78–1.45) [p = 0.70]8.0 [5.0–13.0]8.0 [5.0–12.0]8.0 [5.0–13.0]HR = 1.10 (0.84–1.43) [p = 0.49]Mortality rate at day 9026 (15.0%)12 (13.2%)14 (17.1%)OR = 0.73 (0.31–1.72) [p = 0.47]28 (12.4%)12 (9.8%)16 (15.5%)OR = 0.56 (0.25–1.28) [p = 0.17]SafetyNumber of patients with at least one adverse event Any adverse events96 (42.5%)51 (41.5%)45 (43.7%)OR = 0.90 (0.53–1.54) [p = 0.70] Any grade 1 adverse events20 (8.8%)12 (9.8%)8 (7.8%) Any grade 2 adverse events29 (12.8%)18 (14.6%)11 (10.7%) Any grade 3 adverse events34 (15.0%)18 (14.6%)16 (15.5%) Any grade 4 adverse events35 (15.5%)14 (11.4%)21 (20.4%) Any grade 1 and 2 adverse events43 (19.0%)25 (20.3%)18 (17.5%) Any grade 3 and 4 adverse events63 (27.9%)30 (24.4%)33 (32.0%)OR = 0.67 (0.37–1.20) [p = 0.18]Number of patients with at least one serious adverse event Any serious adverse events60 (26.5%)28 (22.8%)32 (31.1%)OR = 0.63 (0.35–1.15) [p = 0.13] Any serious adverse events leading to outcome of death19 (8.4%)9 (7.3%)10 (9.7%)Data are median [IQR] or n (%).Analyses were stratified on the vaccination status at randomization and adjusted effect measures are reported in the table. For the ordinal scale results, an odds ratio above 1 is in the direction of tixagevimab-cilgavimab being better than placebo. For time to event analyses, a hazard ratio above 1 is in the direction of tixagevimab-cilgavimab being better than placebo. Estimates are reported with their 95% confidence interval. As per the definition in the protocol, adverse events and serious adverse events do not include disease-related events. CI: confidence interval; OR: odds ratio; HR: hazard ratio; BMI: body mass index; ECMO: extracorporeal membrane oxygenation.* 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.+ Only conditions with a relative frequency greater than 10% are displayed in the table.‡ Undetectable viral load values (i.e. values < 1 log10 copies/10 000 cells) were imputed to 0.7 log10 copies/10 000 cells. Open table in a new tab Data are median [IQR] or n (%). Analyses were stratified on the vaccination status at randomization and adjusted effect measures are reported in the table. For the ordinal scale results, an odds ratio above 1 is in the direction of tixagevimab-cilgavimab being better than placebo. For time to event analyses, a hazard ratio above 1 is in the direction of tixagevimab-cilgavimab being better than placebo. Estimates are reported with their 95% confidence interval. As per the definition in the protocol, adverse events and serious adverse events do not include disease-related events. CI: confidence interval; OR: odds ratio; HR: hazard ratio; BMI: body mass index; ECMO: extracorporeal membrane oxygenation. Although T-C combination was safe and well-tolerated, showing no excess cardiac events, it did not significantly improve patients’ clinical status in the DisCoVeRy study, nor accelerate viral clearance, despite a significant increase in neutralizing antibodies against SARS-CoV-2 at days 3 and 8 compared to placebo. The difference with the ACTIV-3-TICO trial concerning mortality is due to the underpowered nature of the DisCoVeRy trial, and possibly amongst other reasons, the changes in infecting SARS-CoV-2 variants. The Delta variant was the predominant one in both trials, but the DisCoVeRy trial enrolled 40% of patients infected with the Omicron variant compared to none in the ACTIV-3-TICO trial.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 Indeed, the SARS-CoV-2 Omicron variant and its multiple sub-lineages have proven to be more than the ancestral or Delta variant to and therapeutic including by in-vitro neutralization 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 due to the Omicron variant have overall proven to be than including S. F. SARS-CoV-2 Omicron recent and 2022; PubMed Scopus Google Scholar patients did hospitalization were at risk of by the mortality rate of at day 90 in trial and the described by Kamboj et 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 early of DisCoVeRy trial, with of the is an of the to in the variant of the COVID-19 to the 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 the of the for immune escape, to an immune the at risk for severe further are needed on to in the clinical to address unmet need by new therapeutic to particularly immunocompromised, while their for evaluating include trials, immune are evaluated in a trial to an is of the on the efficacy of monoclonal antibodies in the context of SARS-CoV-2 variants November 3, Available from: Scholar and the of a global with for in-vitro of antiviral to clinical for Disease and SARS-CoV-2 variant reduced to antiviral drugs and monoclonal a for 2023 November 3, Available from: Scholar antiviral while for vaccination SARS-CoV-2 antibody infecting viral and other better antiviral efficacy of have previously shown with G. N. A. D. G. M. et of on viral in COVID-19 hospitalized a of the randomized, DisCoVeRy 2022; PubMed Scopus Google Scholar from The for the and the for the and for from for on an for on and for for the on for COVID-19 and a for the of and from and from and for from and in a Data and for and from and from and from and for from and from and from the in a Data and for and from and the and from from and from the other authors no from the the and We all participants to in the trial, all and site the of the DisCoVeRy trial in the available on