REGN-COV2 antibody cocktail cuts viral load in COVID-19 outpatients

The REGN-COV2 antibody cocktail containing casirivimab and imdevimab effectively reduced viral load in nonhospitalized patients with COViD-19 — with most profound benefit in those whose immune response to the virus has yet to be initiated, a study has shown. 

The rationale for the treatment stems from the hypothesis “that complications and death from COVID-19 emanate from the SARS-CoV-2 viral burden and that reducing this burden should lead to clinical benefit,” explained the researchers.

“REGN-COV2 is a cocktail made up of two noncompeting, neutralizing human IgG1 antibodies that target the receptor-binding domain of the SARS-CoV-2 spike protein, thereby preventing viral entry into human cells through the ACE2* receptor,” they pointed out.

In the double-blind phase I–II trial, 275 symptomatic nonhospitalized patients (median age 44 years, 49 percent male) with COVID-19 were randomized 1:1:1 to intravenous infusion of REGN-COV2 8.0 g or 2.4 g or saline placebo. [N Engl J Med 2020;doi:10.1056/NEJMoa2035002]

REGN-COV2 led to a greater time-weighted average decrease in viral load (both doses combined) by 0.41 log₁₀ copies/mL through day 7, compared with placebo in the overall population (95 percent confidence interval [CI], -0.71 to -0.10).

Among patients who showed negative serum antibody at baseline, ie, whose own immune response to the virus has yet to be initiated, the time-weighted average decrease in viral load was greater by 0.56 log₁₀ copies/mL compared with placebo (95 percent CI, -1.02 to -0.11).

For the key prespecified endpoint of medical visit for COVID-19, the rate was 6 percent in the placebo group vs 3 percent in the combined REGN-COV2 groups. Again, the difference between treatment groups was greater when the analysis was restricted to serum antibody-negative patients (15 percent vs 6 percent, respectively).

“One possible reason for this observation is that patients whose endogenous immune responses were active (serum antibody–positive) were already efficiently clearing the virus, as compared with patients whose immune response had not yet been initiated (serum antibody–negative),” the researchers explained.

“Our data indicate that REGN-COV2 enhanced clearance of virus, particularly in patients in whom an endogenous immune response had not yet been initiated (ie, serum antibody–negative) or who had a high viral load at baseline,” they observed.

In terms of safety profile of REGN-COV2, the researchers said it was “as expected for a fully human antibody against an exogenous target.” Infusion-related reactions, hypersensitivity reactions, and other adverse events (AEs) occurred at similar rates in the REGN-COV2 and the placebo groups. Serious AEs were rare in both groups.

In context of current scenario

REGN-COV2 was thrust into the limelight as one of the treatments used by former US president Trump in late 2020. It was subsequently granted EUA** for COVID-19 by the US FDA at the end of Nov 2020.

 Another biologic with similar concept of providing antibody to enhance viral clearance was convalescent plasma, which has similarly been granted EUA by the US FDA.

In comparison to convalescent plasma, the researchers said “REGN-COV2 had a profound and rapid effect on viral load, with most reduction occurring within 48 hours.” REGN-COV2 raised neutralizing titres to levels that were >1,000 times of those achievable with convalescent-phase plasma.

“This long half-life of REGN-COV2 suggests that treatment could result in long-term passive immunity for several months,” they added.

“Such monoclonal antibodies may also be successful in preventing SARS-CoV-2 infection as an alternative to vaccination for people who cannot take a vaccine or need more immediate prophylaxis either before or after exposure,” wrote Dr Myron Cohen from the University of North Carolina Chapel Hill School of Medicine, Chapel Hill, North Carolina, US, in a linked editorial. [N Engl J Med 2020;doi:10.1056/NEJMe2034495]

“Such treatments are logistically challenging but should inspire early and rapid testing of persons at high risk for SARS-CoV-2 infection,” he added. “If these drugs prove to provide reliable early treatment of COVID-19, they will greatly improve the management of the infection.”

*ACE2: angiotensin-converting enzyme 2

** EUA: Emergency Use Authorization