Casirivimab and imdevimab combination reduces incidence of symptomatic COVID-19

19th January 2022

Casirivimab and imdevimab in combination have been found to reduce the development of symptomatic COVID-19 over 28 days compared with placebo

Casirivimab and imdevimab used together lead to a significant reduction in the proportion of patients who develop symptomatic COVID-19 compared to those given placebo. This was the conclusion of a randomised trial by researchers from the manufacturer of the combination, Regeneron Pharmaceuticals, New York, US.

Although the arrival of effective COVID-19 vaccines have been shown to boost individuals’ immunity against the virus, therapy with monoclonal antibodies remains an alternative for those who develop an inadequate response to vaccination.

However, a recent Cochrane systematic review of monoclonal antibody therapy in COVID-19, concluded that ‘our certainty in the evidence for all non‐hospitalised individuals is low, and for hospitalised individuals is very low to moderate. We consider the current evidence insufficient to draw meaningful conclusions regarding treatment with SARS‐CoV‐2‐neutralising mAbs‘ (monoclonal antibodies).

Casirivimab and imdevimab are two mAbs that bind to different parts of the spike protein present on the surface of COVID-19. Furthermore, trial data has revealed how this combination reduced the risk of COVID-19–related hospitalisation and all-cause mortality, as well as resolving symptoms and decreasing viral load, more quickly than placebo.

The Regeneron Pharmaceuticals team undertook a two phase study of their combination. In part A, casirivimab and Imdevimab were found to prevent both symptomatic and asymptomatic COVID-19 infection among previously uninfected household contacts of infected individuals.

The present study relates to part B of their trial, in which asymptomatic, infected close contacts were treated with subcutaneous casirivimab and imdevimab.

Part B was a randomised, double-blind, Phase III trial, designed to determine whether subcutaneous casirivimab and imdevimab could prevent progression from asymptomatic to symptomatic infection.

Enrolled participants were adults with a PCR confirmed COVID-19 infection, identified within 96 hours of another household contact testing positive. Included participants were then randomised 1:1 to casirivimab and imdevimab or placebo and the primary endpoint of the trial was the proportion of individuals who developed signs and symptoms of COVID-19 within 14 days of their positive PCR result and this was reviewed over a 28 day period following randomisation.

Findings

A total of 314 individuals with a mean age of 41 years (51.6% female) were included of whom, 204 (66%) were asymptomatic and randomised to either casirivimab and Imdevimab (100) or placebo.

Among asymptomatic individuals assigned to treatment, 29% became symptomatic compared to 42.3% of those given placebo (odds ratio, OR = 0.54, 95% CI 0.30 – 0.97, p = 0.04).

Participants on treatment also experienced a 5.6 day reduction in the mean duration of symptoms compared to placebo and the total number of weeks with a high viral load was significantly reduced (489.9 weeks vs 811.9 weeks per 1000 participants, treatment vs placebo, p = 0.01).

The authors concluded that treatment with casirivimab and imdevimab for asymptomatic COVID-19 positive individuals living with an infected household contact, significantly reduced the incidence of symptomatic infection over a period of 28 days.

Citation

O’Brien MP et al. Effect of Subcutaneous Casirivimab and Imdevimab Antibody Combination vs Placebo on Development of Symptomatic COVID-19 in Early Asymptomatic SARS-CoV-2 Infection. A Randomized Clinical Trial JAMA 2022.

REGEN-COV mortality benefits limited to seronegative COVID-19 patients

21st June 2021

While REGEN-COV contains two monoclonal antibodies binding to different viral sites, it is only effective in seronegative patients.

The use of monoclonal antibodies have been shown to neutralise the COVID-19 virus in cell cultures and produce a significant reduction of viral load in vivo. A combination of two mAbs, casirivimab and imdevimab, which bind to separate parts of the COVID-19 receptor binding domain of the spike protein, are able to block entry of the virus into host cells. Since the mAbs bind to separate sites, there is reduced risk of antiviral failure. The use of this mAbs cocktail, known as REGEN-COV, has been shown to reduce the risk of hospitalisation or death among infected patients, in an outpatient setting. In addition, the manufacturer, Regeneron, has provided initial data which suggests that in hospitalised, seronegative patients, REGEN-COV reduced daily viral load. Whilst encouraging, no anti-viral therapy has been shown to reduce death among those hospitalised with COVID-19. This led the RECOVERY team to undertake a randomised trial of REGEN-COV among seropositive patients, hospitalised with COVID-19. For the trial, eligible patients (those with either clinically suspected or confirmed COVID-19 infection), were randomised in a 1:1:1 ratio to either standard care or standard care plus REGEN-COV or standard care and convalescent plasma. Among patients assigned to REGEN-COV, treatment consisted of a single dose (4g of both mAbs) in 250 ml saline infused over 60 minutes. The primary outcome of the trial was 28-day all-cause mortality and secondary outcomes included the time to discharge from hospital and in those not receiving mechanical ventilation at randomisation, a composite outcome of mechanical ventilation or death.

Findings
A total of 4839 patients were randomised to REGEN-COV and 4946 to usual care. The mean age of study participants was 61.9 years (37% female) and 78% of white ethnicity. However, the complete cohort included 3153 (32%) participants who were seronegative and 5272 (54%) who were seropositive. Among those allocated to REGEN-COV, 24% of seronegative patients and 30% of patients receiving usual care died within 28 days (rate ratio, RR = 0.80, 95% CI 0.70–0.91, p = 0.001).

In an analysis all the whole cohort (irrespective or serological status), 20% of those allocated to REGEN-COV and 21% of those given standard care died within 28 days (RR = 0.94, 95% CL 0.86 – 1.03, p = 0.17). Furthermore, among seronegative patients, progression to mechanical ventilation or death was lower among those receiving REGEN-COV compared to standard care (28% vs 32%).

In discussing their results, the authors noted that there was only an apparent benefit in seronegative patients receiving REGEN-COV. The suggested that the use of REGEN-COV should be restricted to seronegative patients.

Citation
RECOVERY Collaborative Group. Casirivimab and imdevimab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. MedRxiv 2021