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Tixagevimab + Cilgavimab: First Approval.

ABSTRACT: Tixagevimab 150 mg and cilgavimab 150 mg (EVUSHELD^TM 150 mg + 150 mg solution for injection; tixagevimab + cilgavimab) is an intramuscular (IM) long-acting monoclonal antibody combination developed by AstraZeneca for the prevention and treatment of COVID-19. In March 2022, tixagevimab + cilgavimab was approved in the UK for pre-exposure prophylaxis of COVID-19 in adults who are not currently infected with SARS-CoV-2 and who have not had a known recent exposure to an individual infected with SARS-CoV-2 and who are unlikely to mount an adequate immune response to COVID-19 vaccination or for whom COVID-19 vaccination is not recommended, and in the EU for the prevention of COVID-19 in adults and adolescents aged ≥ 12 years and weighing ≥40 kg. In December 2021, tixagevimab + cilgavimab was granted Emergency Use Authorization by the US FDA for the pre-exposure prophylaxis of COVID-19 in adults and paediatric individuals (≥ 12 years of age and weighing ≥ 40 kg). This article summarizes the milestones in the development of tixagevimab + cilgavimab leading to this first approval for pre-exposure prophylaxis of COVID-19 in individuals who are not currently infected with SARS-CoV-2.

SUBMITTER: Keam SJ

PROVIDER: S-EPMC9211051 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Tixagevimab + Cilgavimab: First Approval.

Keam Susan J SJ

Drugs 20220601 9

Tixagevimab 150 mg and cilgavimab 150 mg (EVUSHELD<sup>TM</sup> 150 mg + 150 mg solution for injection; tixagevimab + cilgavimab) is an intramuscular (IM) long-acting monoclonal antibody combination developed by AstraZeneca for the prevention and treatment of COVID-19. In March 2022, tixagevimab + cilgavimab was approved in the UK for pre-exposure prophylaxis of COVID-19 in adults who are not currently infected with SARS-CoV-2 and who have not had a known recent exposure to an individual infecte ...[more]

PMID: 35727563

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Project description:BackgroundThe monoclonal-antibody combination AZD7442 is composed of tixagevimab and cilgavimab, two neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that have an extended half-life and have been shown to have prophylactic and therapeutic effects in animal models. Pharmacokinetic data in humans indicate that AZD7442 has an extended half-life of approximately 90 days.MethodsIn an ongoing phase 3 trial, we enrolled adults (≥18 years of age) who had an increased risk of an inadequate response to vaccination against coronavirus disease 2019 (Covid-19), an increased risk of exposure to SARS-CoV-2, or both. Participants were randomly assigned in a 2:1 ratio to receive a single dose (two consecutive intramuscular injections, one containing tixagevimab and the other containing cilgavimab) of either 300 mg of AZD7442 or saline placebo, and they were followed for up to 183 days in the primary analysis. The primary safety end point was the incidence of adverse events after a single dose of AZD7442. The primary efficacy end point was symptomatic Covid-19 (SARS-CoV-2 infection confirmed by means of reverse-transcriptase-polymerase-chain-reaction assay) occurring after administration of AZD7442 or placebo and on or before day 183.ResultsA total of 5197 participants underwent randomization and received one dose of AZD7442 or placebo (3460 in the AZD7442 group and 1737 in the placebo group). The primary analysis was conducted after 30% of the participants had become aware of their randomized assignment. In total, 1221 of 3461 participants (35.3%) in the AZD7442 group and 593 of 1736 participants (34.2%) in the placebo group reported having at least one adverse event, most of which were mild or moderate in severity. Symptomatic Covid-19 occurred in 8 of 3441 participants (0.2%) in the AZD7442 group and in 17 of 1731 participants (1.0%) in the placebo group (relative risk reduction, 76.7%; 95% confidence interval [CI], 46.0 to 90.0; P<0.001); extended follow-up at a median of 6 months showed a relative risk reduction of 82.8% (95% CI, 65.8 to 91.4). Five cases of severe or critical Covid-19 and two Covid-19-related deaths occurred, all in the placebo group.ConclusionsA single dose of AZD7442 had efficacy for the prevention of Covid-19, without evident safety concerns. (Funded by AstraZeneca and the U.S. government; PROVENT ClinicalTrials.gov number, NCT04625725.).

Project description:Background Pre-exposure prophylaxis for COVID-19 with tixagevimab/cilgavimab (T/C) received Emergency Use Authorization (EUA) based on results of a clinical trial conducted prior to the emergence of the Omicron variant. The clinical effectiveness of T/C has not been well described in the Omicron era. We examined the incidence of symptomatic illness and hospitalizations among T/C recipients when Omicron accounted for virtually all local cases. Methods Through retrospective electronic medical record chart review, we identified patients who received T/C between January 1 –July 31, 2022 within our quaternary referral health system. We determined the incidence of symptomatic COVID-19 infections and hospitalizations due to or presumed to be caused by early Omicron variants before and after receiving T/C (pre-T/C and post-T/C). Chi square and Mann-Whitney Wilcoxon two-sample tests were used to examine differences between the characteristics of those who got COVID-19 before or after T/C prophylaxis, and rate ratios (RR) and 95% confidence intervals (CI) were calculated to assess differences in hospitalization rates for the two groups. Results Of 1295 T/C recipients, 105 (8.1%) developed symptomatic COVID-19 infection before receiving T/C, and 102 (7.9%) developed symptomatic disease after receiving it. Of the 105 patients who developed symptomatic infection pre-T/C, 26 (24.8%) were hospitalized, compared with six of the 102 patients (5.9%) who were diagnosed with COVID-19 post-T/C (RR = 0.24; 95% CI = 0.10–0.55; p = 0.0002). Seven of the 105 (6.7%) patients infected pre-T/C, but none of the 102 infected post-T/C required ICU care. No COVID-related deaths occurred in either group. The majority of COVID-19 cases among those infected pre-T/C treatment occurred during the Omicron BA.1 surge, while the majority of post-T/C cases occurred when Omicron BA.5 was predominant. In both groups, having at least one dose of vaccine strongly protected against hospitalization (pre-T/C group RR = 0.31, 95% CI = 0.17–0.57, p = 0.02; post-T/C group RR = 0.15; 95% CI = 0.03–0.94; p = 0.04). Conclusion We identified COVID-19 infections after T/C prophylaxis. Among patients who received T/C at our institution, COVID-19 Omicron cases occurring after T/C were one-fourth as likely to require hospitalization compared to those with Omicron prior to T/C. However, due to the presence of changing vaccine coverage, multiple therapies, and changing variants, the effectiveness of T/C in the Omicron era remains difficult to assess.

Project description:Therapeutic anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) monoclonal antibodies (MAbs) provide immunosuppressed and vulnerable populations with prophylactic and treatment interventions against coronavirus disease 2019 (COVID-19). AZD7442 (tixagevimab-cilgavimab) is a combination of extended-half-life neutralizing MAbs that bind to distinct epitopes on the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. The Omicron variant of concern carries mutations at >35 positions in the spike protein and has undergone further genetic diversification since its emergence in November 2021. Here, we characterize the in vitro neutralization activity of AZD7442 toward major viral subvariants circulating worldwide during the first 9 months of the Omicron wave. BA.2 and its derived subvariants showed the highest susceptibility to AZD7442, while BA.1 and BA.1.1 showed a lower susceptibility. BA.4/BA.5 had a susceptibility level intermediate between BA.1 and BA.2. Mutagenesis of parental Omicron subvariant spike proteins was performed to establish a molecular model to describe the underlying determinants of neutralization by AZD7442 and its component MAbs. The concurrent mutation of residues at positions 446 and 493, located in the tixagevimab and cilgavimab binding sites, was sufficient to enhance in vitro susceptibility of BA.1 to AZD7442 and its component MAbs to levels similar to the Wuhan-Hu-1+D614G virus. AZD7442 maintained neutralization activity against all Omicron subvariants tested up to and including BA.5. The evolving nature of the SARS-CoV-2 pandemic warrants continuing real-time molecular surveillance and assessment of in vitro activity of MAbs used in prophylaxis against and the treatment of COVID-19. IMPORTANCE MAbs are key therapeutic options for COVID-19 prophylaxis and treatment in immunosuppressed and vulnerable populations. Due to the emergence of SARS-CoV-2 variants, including Omicron, it is vital to ensure that neutralization is maintained for MAb-based interventions. We studied the in vitro neutralization of AZD7442 (tixagevimab-cilgavimab), a cocktail of two long-acting MAbs targeting the SARS-CoV-2 spike protein, toward Omicron subvariants circulating from November 2021 to July 2022. AZD7442 neutralized major Omicron subvariants up to and including BA.5. The mechanism of action responsible for the lower in vitro susceptibility of BA.1 to AZD7442 was investigated using in vitro mutagenesis and molecular modeling. A combination of mutations at two spike protein positions, namely, 446 and 493, was sufficient to enhance BA.1 susceptibility to AZD7442 to levels similar to the Wuhan-Hu-1+D614G ancestral virus. The evolving nature of the SARS-CoV-2 pandemic warrants continuing real-time global molecular surveillance and mechanistic studies of therapeutic MAbs for COVID-19.

Project description:BackgroundImmunocompromised individuals are at high risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and subsequent severe or fatal coronavirus disease 2019 (COVID-19), yet they have suboptimal responses to mRNA and inactivated COVID-19 vaccines. The efficacy of tixagevimab-cilgavimab in reducing symptomatic SARS-CoV-2 infection was demonstrated in phase III clinical trials. Nevertheless, real-world data on the effectiveness and safety of tixagevimab-cilgavimab remain limited.ObjectiveThe aim was to evaluate the effectiveness and safety of tixagevimab-cilgavimab among immunocompromised individuals.MethodsAdults who were immunocompromised or receiving immunosuppressive therapies were included in this target trial emulation using territory-wide electronic health records in Hong Kong. A sequential trial emulation approach was adopted to compare effectiveness and safety outcomes between individuals who received tixagevimab-cilgavimab and individuals who did not.ResultsA total of 746 tixagevimab-cilgavimab recipients and 2980 controls were included from 1 May 2022 to 30 November 2022. Tixagevimab-cilgavimab significantly reduced the risk of COVID-19 infection (hazard ratio [HR] 0.708, 95% confidence interval [CI] 0.527-0.951) during a median follow-up of 60 days. No significant difference was observed in the risk of COVID-19-related hospitalisation. Zero versus eight COVID-19 mortality cases and zero versus two severe COVID-19 cases were observed in tixagevimab-cilgavimab recipients and controls, respectively. Notably, significant risk reduction in COVID-19 infection was also observed among immunocompromised individuals who had been previously vaccinated with three or more doses of COVID-19 vaccine, or had no prior COVID-19 infection history.ConclusionsTixagevimab-cilgavimab was effective in reducing COVID-19 infection among immunocompromised patients during the Omicron wave. Findings were consistent among individuals who previously received three or more doses of COVID-19 vaccine, or had no previous history of COVID-19 infection.

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Tixagevimab + Cilgavimab: First Approval.

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Tixagevimab + Cilgavimab: First Approval.

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