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24th June 2022
A single dose of Evusheld given to non-hospitalised, unvaccinated patients experiencing mild to moderate COVID-19 led to a significant reduction in progression to more severe disease (i.e., hospitalisation) and mortality compared to those given placebo. These were the key findings from the the TACKLE study by a group of UK and US researchers.
Evusheld contains the two monoclonal antibodies, tixagevimab and cilgavimab, which simultaneously bind to distinct, non-overlapping epitopes on the spike protein receptor binding domain and are therefore able to neutralise COVID-19. It is administered as a single intra-muscular dose and in March 2022, the EMA granted a marketing authorisation for Evusheld for the prevention of COVID-19 in adults and adolescents from 12 years of age weighing at least 40kg before potential exposure to the virus.
The combination of monoclonal antibodies has been examined in TACKLE, which is an ongoing, Phase III randomised, double-blind trial conducted in 95 sites across the USA, Latin America, Europe and Japan. Included patients are adults (18 years and over) with a documented, laboratory confirmed PCR or antigen test, COVID-19 infection, at least 3 days before enrolment in the trial. An additional entry requirement is a score of > 1 but less than 4 on the World Health Organization (WHO) Clinical progression Scale.
For the study, all eligible participants were randomised 1:1 to a single dose of Evusheld (600mg, which consists of two consecutive doses of 300mg of each) or saline solution (which served as the placebo) on the first day of the trial. The primary outcome of the study was a composite endpoint of either severe COVID-19, defined by either the presence of pneumonia, hypoxaemia plus a WHO scale score of 5 and higher or all-cause mortality.
Single dose of Evusheld and COVID-19 outcomes
A total of 903 participants with mean age of 46.1 years (50% female) were enrolled and randomised to evusheld (452) or placebo. Just over half (52%) of participants were of Hispanic or Latino ethnicity with 62% being White and 4% Black or African American. A total of 89% of the entire cohort had at least one or more risk factors for severe COVID-19 including a body mass index > 30 (43%), hypertension (28%), current smokers (40%) and diabetes (12%).
The primary endpoint (severe COVID-19 or death) occurred in 4% of those receiving a single dose of Evusheld and in 9% of those given a placebo and this difference was significant (absolute risk reduction = 4.5%, 95% CI 1.1 – 8.0, p < 0.0001).
In terms of safety, adverse effects occurred in 29% of those given Evusheld and 36% of those using placebo and most were deemed to be of mild or moderate severity.
The authors concluded that a single dose of Evusheld was associated with a statistical and clinically meaningful reduction in both progression to more severe COVID-19 and death compared with placebo among unvaccinated adult patients.
Montgomery H 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
25th March 2022
Tixagevimab/cilgavimab (Evusheld) is a combination of two monoclonal antibodies that has been approved by the UK’s MHRA for use before exposure to COVID-19 in order to prevent the disease. The drug would therefore be most suited to adult patients who are unable to mount a sufficient immune response after receiving a COVID-19 vaccination or alternatively, patients for whom vaccination is not recommended.
Evusheld was issued an emergency use authorisation (EUA) by the FDA in the US in December 2021 for the pre-exposure prophylaxis (prevention) of COVID-19 in certain adults and paediatric individuals (12 years of age and older weighing at least 40 kilograms. However, the combination would not be suitable for those currently infected with COVID-19 or who have had a recent and known exposure to someone infected with the virus. The two components of Evusheld are available as separate intramuscular injections and research has shown that these recognise non-overlapping sites and are simultaneously bound to the S protein and neutralise the wild-type COVID-19 virus in a synergistic manner. As a result, the manufacturer, AstraZeneca, has examined the value of Evusheld in three separate clinical studies.
Evusheld clinical efficacy
To date, none of the three major clinical studies have been fully published and the efficacy data has been made available in press releases from the manufacturer. Evusheld was examined in the PROVENT trial which was designed to assess the safety and efficacy of a single dose compared to placebo for the prevention of COVID-19. The trial included 5,197 participants and who were randomised 2:1 to a single 300 mg dose of Evusheld (AZD7442 in all press releases) or placebo and which was administered in two separate, sequential IM injections. The trial recruited individuals 18 years of age and over (including 43% who were older than 60 years of age) who would benefit from prevention and were defined as having an increased risk for an inadequate response to active immunisation or having an increased risk for COVID-19 infection. Participants at the time of screening were unvaccinated and had a negative COVID-19 test. The primary efficacy endpoint of the trial was the first case of any COVID-19 PCR confirmed, symptomatic illness occurring after the dose before day 183. According to a press release from the manufacturer, Evusheld reduced the risk of developing symptomatic COVID-19 by 77% (95% CI 46 – 90%) in comparison to those given a placebo.
A second trial, STORM CHASER, was designed to explore post-exposure prophylaxis of COVID-19 in Adult patients. The trial included 1,121 participants, randomised 2:1 as before to either Evusheld or placebo, all of whom tested negative for COVID-19 prior to receiving treatment. Again, in a press release from the manufacturer, Evusheld reduced the risk of developing symptomatic COVID-19 by 73% (95% CI 27 – 90%) compared with placebo among those who were PCR negative at the time of dosing.
The third trial, TACKLE, explored the value of Evusheld given to adults who were non-hospitalised with mild-to-moderate COVID-19 and symptomatic for seven days or less, but this time, given a 600 mg dose of the drug. The primary efficacy endpoint of the trial was the composite of either severe COVID-19 or death from any cause through day 29. According to the manufacturer press release on TACKLE, Evusheld given to participants within five days of symptom onset, saw a 67% reduced risk of developing severe COVID-19 or death compared to placebo.
On the basis of these findings, the MHRA has approved the drug and in Europe, the EMA is currently evaluating the combination.