Coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has evolved into a pandemic that has resulted in the global destruction of life and economies. Numerous therapeutics had received emergency use authorization (EUA) for treating COVID-19 and REGEN-COV is one of them. Therefore, it is imperative that the effects of these therapies granted EUA be investigated in clinical trials against COVID-19. REGEN-COV is formulated as a combination of the monoclonal antibodies casirivimab and imdevimab.
The phase 1-2 clinical trials conducted using REGEN-COV had shown promising therapeutic benefits in COVID-19 outpatients. Its effect was further investigated in the present phase 3 clinical trial, the findings of which have been published in the "The New England Journal of Medicine".
Trial design
The present trial was a phase 1–3 adaptive, multicenter, double-blind, randomized, placebo-controlled trial. The current phase 3 trial was conducted on outpatients suffering from COVID-19 who were segregated into three cohorts. Cohort 1 consisted of patients who were ≥18 years of age, cohort 2 included patients who were <18 years of age, and cohort 3 consisted of women who were pregnant at the time of randomization.
Initially, in the trial, the patients were randomized in a 1:1:1 ratio to receive intravenous (IV) dose of REGEN-COV at a dose of 2,400 mg comprising of 1,200 mg each of casirivimab and imdevimab or 8,000 mg containing 4,000 mg each of constituent antibodies or placebo. However, based on the results of phases 1 and 2, the trial was amended on November 14, 2020, wherein patients with at least one risk factor for developing severe COVID-19 were only enrolled in the trial as most of the clinical events were observed only in high-risk patients.
Further, the dose of REGEN-COV was changed such that the higher dose of REGEN-COV 8.000 mg was removed as it had produced similar effects to 2.400 mg, and patients were randomized 1:1:1 to receive REGEN-COV either at a dose of 1.200 mg or 2.400 mg or placebo.
The present findings are phase 3 primary efficacy analysis on cohort 1, and studies with cohorts 2 and 3 are still ongoing.
Study population
Population in cohort 1 comprised of outpatients 18 years or older who had a positive local diagnosis test for SARS-CoV-2 which should have been taken not more than 72 hrs before randomization. They should also exhibit any COVID-19 symptoms, which were observed no more than 7 days before randomization.
Initially, the patients were stratified according to country and risk factors for COVID-19. However, after the trial was amended, only patients with at least one risk factor for developing severe COVID-19 were included.
Presence of anti–SARS-CoV-2 antibodies; anti-spike (S1) IgA, anti-spike (S1) IgG, and anti-nucleocapsid IgG were assessed in these patients at baseline and based on the results they were categorized as serum antibody-negative, serum antibody -positive or other if their test results were inconclusive.
Primary and secondary endpoints assessed in the trial
The primary clinical endpoint in the trial was at least one COVID-19 related hospitalization or death from any cause during the 29 day follow-up period.
The secondary clinical endpoints were at least one COVID-19 related hospitalization or death from any cause from day 4 to day 29 and time taken for COVID-19 symptom resolution.
The vaccine's safety was also evaluated by assessing endpoints, which included serious adverse events and specific adverse events of interest like hypersensitivity events of grade 2 or higher, infusion-related events, and other events that required medical attention.
REGEN-COV reduced risk of hospitalization, death and caused faster attenuation of COVID-19 symptoms
The findings from the phase 3 trial showed that in COVID-19 outpatients with risk factors for developing severe disease, early REGEN-COV administration reduced the risk of hospitalization or death due to any cause. This is in corroboration with the phase 1-2 clinical trial findings that showed that REGEN-COV decreased viral load, need for medical assistance for COVID-19 related events, and hospitalization risk. Both the doses of IV REGEN-COV tested, 1,200 mg and 2,400 mg resulted in reduced COVID-19 related hospitalization and death during the follow-up period of 28 days after administration. In hospitalized patients, REGEN-COV reduced the duration of hospitalization and the incidence of ICU admissions. In addition, when both doses were tested, REGEN-COV resulted in faster attenuation of symptoms than placebo by a median time of 4 days.
Single-dose REGEN-COV therapy to COVID-19 outpatients may effectively reduce morbidity like hospitalizations and ICU admissions and confer speedy recovery from COVID-19, preventing the prolonged recovery periods associated with COVID-19 infection.
REGEN-COV reduced viral load in COVID-19 patient population in the study
REGEN-COV at both doses tested improved health outcomes and produced significant clinical benefits regardless of the baseline serum antibody status. Both the doses tested produced a faster reduction in viral load and produced similar clinical benefits.
The findings from the trial show that in patients in the placebo group who had high viral loads at baseline, there was an increased incidence of COVID-19 associated hospitalizations and death. Further, these patients cleared the viral load more slowly than others who did not require hospitalization and who survived.
In phase 1-2 of the trial, patients who were tested at baseline to be serum antibody-negative had a higher incidence of visits for medical assistance than serum-positive patients. However, in the phase 3 trial, there was no difference in hospitalizations or death based on their serum antibody status in the placebo population. This may suggest a possibility of an inadequate immune response in serum antibody-positive patients who suffered COVID-19 related hospitalizations or died. It was observed that these patients had a high baseline viral load similar to the serum antibody-negative population.
It was found that the serum concentration of the antibodies was maintained at levels higher than that predicted to be required for neutralization during the period from the end of infusion until day 29.
REGEN-COV exhibited good safety profile
The adverse events that were observed during the trial were primarily COVID-19 complications and were not associated with the trial drug. Infusion-related reactions of grade 2 or higher, hypersensitivity reactions, and serious adverse events were observed in a small number of patients in the study population.
Implications of the present study
In the present phase-3 clinical trial, REGEN-COV at both 1,200 mg and 2,400 mg doses reduced the risk of COVID-19 related hospitalizations or death from any cause. It effectively and rapidly attenuated COVID-19 related symptoms and produced a speedy reduction of SARS-CoV-2 viral load in comparison to placebo.
REGEN-COV at the dose of 2,400 mg received emergency use authorization in November 2021. After the findings from this trial were released, the 1,200 mg dose was authorized to replace the 2,400 mg dose for emergency use in June 2021 as both doses provided similar benefits.
The Combination therapies with non-competing antibodies have been found to suppress the evolution of resistant variants in in vitro and in vivo animal studies. REGENOV-COV formulated as a combination of monoclonal antibodies casirivimab and imdevimab when tested in-vitro interestingly showed an antiviral effect on SARS-CoV-2 variants like B.1.1.7 (alpha), B.1.351 (beta), B.1.617.2 (delta), and P.1 (gamma).
The findings from this phase 3 clinical trial show that REGEN-COV is an effective therapy against SARS-CoV-2, and it has been included for the treatment of high-risk COVID-19 outpatients by the National Institute of Health (NIH) treatment guidelines.
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