Early treatment with the monoclonal antibody duo tixagevimab-cilgavimab (Evusheld) as post-exposure prophylaxis halved the rate of severe COVID-19 or death in unvaccinated patients at high risk of progression to severe disease, a Phase III trial has shown.
The product, which is currently available in Australia for pre- but not post-exposure prophylaxis in high-risk patients, is a combination of two long-acting antibodies derived from B-cells donated by convalescent patients after SARS-CoV-2 infection.
In the ongoing study, which is being funded by Evusheld manufacturer AstraZeneca, unvaccinated, non-hospitalised adults with confirmed SARS-CoV-2 infection three days or less before enrolment (between January and July 2021), and a WHO Clinical Progression Score of between 1 and 4, were randomised to receive either a single tixagevimab-cilgavimab 600 mg dose by intramuscular injection or placebo.
Severe COVID-19 or death was recorded in 18 (4%) of 407 participants in the tixagevimab-cilgavimab group, compared to 37 (9%) of 415 participants in the placebo group, which equated to a relative risk reduction of 51%.
Crucially, the data, published in The Lancet Respiratory Medicine, showed that the effect of Evusheld was greatest when used early; in participants who received the treatment within three days of symptom onset, the risk of developing severe COVID-19 or death (from any cause) was reduced by 88% versus placebo, but this dropped to 67% in those who received Evusheld within five days of symptom onset.
Evusheld also cut the risk of respiratory failure by 72%, with three patients given the treatment (0.7%) versus 11 given the placebo (3%) requiring measures such as mechanical ventilation or extracorporeal membrane oxygenation during the trial.
On the safety side, Evusheld was generally well tolerated, with more adverse events (AEs) observed in the placebo arm (36% versus 29%, respectively). The most common was pneumonia (11% versus 6%, respectively), while serious AEs occurred in 12% of the placebo group and 7% in the Evusheld group.
According to the authors, “tixagevimab–cilgavimab administered intramuscularly presents a potential additional option for treating mild to moderate COVID-19 in individuals at high risk, and contributes to the armamentarium against COVID-19, which is crucial for reducing the burden on health-care systems”.
However, they also highlight several limitations of the study, including a low proportion of Black and African American and Asian participants, the exclusion of individuals previously vaccinated against COVID-19, and the low number of immunocompromised individuals and older adults.
In a linked comment, Dr Myron Cohen, co-chair of the HIV Prevention Trials Network and COVID Prevention Network, said that the potential use of tixagevimab-cilgavimab for treatment of early COVID-19 “must be put into context”.
At present the most popular treatment for COVID-19 for those at risk of progression is an oral combination of nirmatrelvir plus the CYP3A4 inhibitor, ritonavir (Paxlovid), for five days within five days of symptom onset.
Oral agents have a “crucial advantage”, in that “they can be expected to work against all circulating variants because they are not affected by mutations in the viral proteins that compromise neutralisation by monoclonal antibodies, and they require no administration by a health-care provider”, he said.
However, “it is possible that combination treatments will be required for some compromised hosts, and the idea of a monoclonal antibody such as tixagevimab-cilgavimab, combined with an oral medication is a provocative option”.
“The best management of SARS-CoV-2 is still in development. Tixagevimab-cilgavimab and newer monoclonal antibodies and oral antiviral agents are examples of the many tools that will be needed.”
Evushield is available from the National Stockpile but the National (Australian) COVID-19 Clinical Evidence Taskforce says it should only be considered in exceptional circumstances, for pre-exposure prophylaxis in individuals who are severely immunocompromised and at high risk of progression to severe COVID-19.
This includes people who are expected to have an inadequate response to vaccination, who have solid organ transplant, blood or bone marrow transplant; primary immune deficiencies; secondary immune deficiencies, including patients on significant immunosuppressive medications and some people with HIV.