Tixagevimab 150mg/1.5ml solution for injection vials

BACKGROUND: During the COVID-19 pandemic, some populations, including immunocompromised patients, could not tolerate COVID-19 vaccination or had low responses. Evusheld is a combined neutralizing monoclonal antibody containing tixagevimab and cilgavimab. The World Health Organization (WHO) has approved this combination as pre-exposure prophylaxis (PrEP) and treatment for immunocompromised patients. With the new variant, the (WHO) recommended an increase in dose from 300 to 600 mg with a booster dose after 6 months. The target of this review was to compare the efficacy of the two doses, 300 mg and 600 mg of tixagevimab/cilgavimab (Evusheld) as prophylaxis for higher-risk individuals to reveal if there is a significant difference in efficacy between those two doses of the drug. METHODS: In this study, electronic databases (PubMed, Web of Science core collection, Scopus, and Cochran) were investigated for articles up to 31/12/2022 in English using a well-established search strategy. We included studies conducted in immunocompromised patients (aged ≥ 12 years) (WHO) received Evusheld as prophylaxis or treatment for COVID-19. After excluding studies inconsistent with the selection criteria, 24 were involved, 22 of which were included in the meta-analysis. We analyzed the data by using RevMan 5.4 program software. RESULTS: In the double-arm subgroup analysis, Evusheld 600 mg, administered as prophylaxis, showed no significant difference in the COVID-19 infection rate, mortality rate, or needed hospitalization rate compared with the dose of 300 mg (p = 0.13, p = 0.29, and p = 0.25, respectively). In the single-arm subgroup analysis, Evusheld 600 mg, administered as prophylaxis, showed a significant decrease in the COVID-19 infection rate and the hospitalization rate compared with the dose of 300 mg (p = 0.0001, p = 0.007, respectively). As a treatment, Evusheld showed a significant decrease in the mortality rate over the placebo group (p = 0.01) in COVID-19 patients. CONCLUSION: This result indicated that Evusheld was an effective prophylactic and therapeutic drug for COVID-19 infection, especially for immunocompromised patients, but there was no considerable variation between the high and low doses. Further prospective and randomized controlled trials (RCTs) with increased population sizes are necessary to show the valuable benefit of the high dose of Evusheld in COVID-19 prevention and treatment and to compare the difference between the two doses within adverse events.

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Background: Tixagevimab/cilgavimab (Tix/Cil) shows promise as a prophylactic treatment against coronavirus disease 2019 (COVID-19) in solid organ transplant recipients (SOTRs). This study was performed to assess the effectiveness of Tix/Cil for preexposure prophylaxis against COVID-19 in this population. Methods: We systematically searched the Cochrane Library, Web of Science, PubMed, and Embase databases to identify articles relevant to our study up to December 15, 2023. Comprehensive Meta-Analysis (ver. 3.0) was used for data analysis. Results: The meta-analysis included seven eligible retrospective studies, encompassing a total of 4,026 SOTRs. The analysis revealed significant differences in SOTRs who received Tix/Cil preexposure prophylaxis relative to those who did not. Specifically, these differences were observed in the incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (odds ratio [OR], 0.30; 95% confidence interval [CI], 0.15-0.60), hospitalization (OR, 0.24; 95% CI, 0.08-0.70), and intensive care unit admission (OR, 0.07; 95% CI, 0.02-0.22). However, mortality rate did not differ significantly between the two groups (P=0.06). Conclusions: The evidence supporting the effectiveness of Tix/Cil as preexposure prophylaxis against SARS-CoV-2 in SOTRs is of a low to moderate level. Further high-quality research is necessary to understand its effects on this population.

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BACKGROUND: This meta-analysis addresses the efficacy and safety of tixagevimab-cilgavimab as pre-exposure prophylaxis against COVID-19 in immunocompromised patients, particularly during the Omicron variant surge. Given the limited vaccine response in this population, alternative prophylactic strategies are critical. METHODS: Following PRISMA guidelines, we comprehensively searched electronic databases, including PubMed, Scopus, Web of Science, and Embase, up to June 22, 2024. We included studies assessing tixagevimab-cilgavimab's impact on SARS-CoV-2 infection rates, hospitalization, ICU admissions, and/or mortality among immunocompromised patients. Data synthesis and analysis were conducted using RevMan and Open-Meta Analyst software. RESULTS: Analyzing data from 36 studies involving 28,950 patients, tixagevimab-cilgavimab significantly reduced SARS-CoV-2 infection rates by 4.37%, hospitalization by 0.8%, and mortality by 0.5%. Compared to no prophylaxis, the drug combination showed a notable reduction in SARS-CoV-2 infection (OR = 0.33, 95% CI: 0.22-0.50), hospitalization (OR = 0.24, 95% CI: 0.15-0.39), and mortality (OR = 0.33, 95% CI: 0.16-0.66), exhibiting a favorable safety and efficacy profile. During the Omicron surge, tixagevimab-cilgavimab consistently reduced infection risk (OR = 0.32, 95% CI: 0.17-0.58). CONCLUSION: Tixagevimab-cilgavimab offers a significant protective effect against COVID-19, including Omicron variants, in immunocompromised patients, underscoring its role as an effective pre-exposure prophylaxis. Future studies should further explore its efficacy across different SARS-CoV-2 variants and potential synergies with vaccination efforts.

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Evusheld® (tixagevimab + cilgavimab; AZD7442) was the first anti-Spike monoclonal antibody (mAb) cocktail designed not only for treatment but also with pre-exposure prophylaxis in mind. The immunoglobulins were engineered for prolonged half-life by modifying the Fc fragment, thus creating a long-acting antibody (LAAB). We review here preclinical development, baseline and treatment-emergent resistance, clinical efficacy from registration trials, and real-world post-marketing evidence. The combination was initially approved for pre-exposure prophylaxis at the time of the SARS-CoV-2 Delta VOC wave based on a trial conducted in unvaccinated subjects when the Alpha VOC was dominant. Another trial also conducted at the time of the Alpha VOC wave proved efficacy as early treatment in unvaccinated patients and led to authorization at the time of the BA.4/5 VOC wave. Tixagevimab was ineffective against any Omicron sublineage, so cilgavimab has so far been the ingredient which has made a difference. Antibody monotherapy has a high risk of selecting for immune escape variants in immunocompromised patients with high viral loads, which nowadays represent the main therapeutic indication for antibody therapies. Among Omicron sublineages, cilgavimab was ineffective against BA.1, recovered efficacy against BA.2 and BA.2.12.1, but lost efficacy again against BA.4/BA.5 and BA.2.75. Our analysis indicated that Evusheld® has been used during the Omicron VOC phase without robust clinical data of efficacy against this variant and suggested that several regulatory decisions regarding its use lacked consistency. There is an urgent need for new randomized controlled trials in vaccinated, immunocompromised subjects, using COVID-19 convalescent plasma as a control arm.

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Abstract Background Tixagevimab and cilgavimab (AZD7442) are two monoclonal antibodies developed by AstraZeneca for the pre-exposure prophylaxis and treatment of patients infected by SARS-CoV-2. Its effectiveness and safety in patients hospitalized with COVID-19 was not known at the outset of this trial. Methods DisCoVeRy is a phase 3, adaptive, multicentre, randomized, controlled trial conducted in 63 sites in Europe. Participants were randomly assigned (1:1) to receive placebo or tixagevimab-cilgavimab in addition to standard of care. The primary outcome was the clinical status at day 15 measured by the WHO seven-point ordinal scale. Several clinical, virological, immunological and safety endpoints were also assessed. Findings Due to slow enrolment, recruitment was stopped on July 1 st , 2022. The antigen positive modified intention-to-treat population (mITT) was composed of 173 participants randomized to tixagevimab-cilgavimab (N = 91) or placebo (N = 82), 91.9% (159/173) with supplementary oxygen, and 47.4% (82/173) previously vaccinated at inclusion. There was no significant 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. In the global mITT (N = 226), neutralization antibody titers were significantly higher in the tixagevimab-cilgavimab group/patients compared to placebo at day 3 (Least-squares mean differences (LSMD) 1.44, 95% Confidence interval (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 most important 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). Interpretation There were no significant differences between tixagevimab-cilgavimab and placebo in clinical endpoints, however the trial lacked power compared to prespecified calculations. Tixagevimab-cilgavimab was well tolerated, with low rates of treatment related events. Funding Trial registration: ClinicalTrials.gov NCT04315948 . Registered on 13 March 2020 updated on 22 April 2021.

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ABSTRACT AZD7442 is a combination of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-neutralizing antibodies, tixagevimab and cilgavimab, developed for pre-exposure prophylaxis (PrEP) and treatment of coronavirus disease 2019 (COVID-19). Using data from eight clinical trials, we describe a population pharmacokinetic (popPK) model of AZD7442 and show how modeling of “interim” data accelerated decision-making during the COVID-19 pandemic. The final model was a two-compartmental distribution model with first-order absorption and elimination, including standard allometric exponents for the effect of body weight on clearance and volume. Other covariates included were as follows: sex, age >65 years, body mass index ≥30 kg/m 2 , and diabetes on absorption rate; diabetes on clearance; Black race on central volume; and intramuscular (IM) injection site on bioavailability. Simulations indicated that IM injection site and body weight had > 20% effects on AZD7442 exposure, but no covariates were considered to have a clinically relevant impact requiring dose adjustment. The pharmacokinetics of AZD7442, cilgavimab, and tixagevimab were comparable and followed linear kinetics with extended half-lives (median 78.6 days for AZD7442), affording prolonged protection against susceptible SARS-CoV-2 variants. Comparison of popPK simulations based on “interim data” with a target concentration based on 80% viral inhibition and assuming 1.81% partitioning into the nasal lining fluid supported a decision to double the PrEP dosage from 300 mg to 600 mg to prolong protection against Omicron variants. Serum AZD7442 concentrations in adolescents weighing 40–95 kg were predicted to be only marginally different from those observed in adults, supporting authorization for use in adolescents before clinical data were available. In these cases, popPK modeling enabled accelerated clinical decision-making.

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