Reference: Chen P, Nirula A, Heller B, et al. NEJM Oct 28, 2020; DOI: 10.1056/NEJMoa2029849
Author: Surabhi (Sara) Vora, MD, MPH, Associate Professor of Pediatrics, Division of Infectious Diseases, Seattle Childrens’s Hospital
Reviewers: Joshua Wolf MBBS, PhD, FRACP, Ramatu Mohammed-Nafi’u, BSC, MBBS, FWACP, FMCP(Consultant Paediatrician)
Background: SARS-CoV-2 infection continues to surge globally and no effective therapeutics are available for mild or moderate disease. Until an effective vaccine becomes widely available, a strategy for preventing progression to serious disease in high-risk individuals is desirable.
Methods and Results: This was a Phase 2, randomized, double-blind, placebo-controlled trial conducted at 41 centers in the United States. Patients included adults (median age 45) with one or more symptoms of mild to moderate COVID-19 infection with a median of 4 days since symptom onset. Patients were randomized to receive either LY-CoV555 (700 mg, 2800 mg or 7000 mg), a monoclonal antibody that recognizes the SARS-CoV-2 spike protein, or placebo. The primary outcome of interest was change in SARS-CoV-2 viral load by day 11 (+/-4 days) after initial positive result. Secondary outcomes included safety, clinical symptoms, subsequent hospitalizations or ED visits (combined for this analysis), and mortality. This manuscript describes a pre-planned interim analysis for the study.
309 patients received Ly-CoV555 (divided evenly between dose groups) and 143 patients received placebo; 70% had ≥ one risk factor for severe disease (age >65, BMI > 35, or underlying condition). At Day 11, participants who received LY-CoV555 had a greater reduction in viral load (mean Log10 viral load difference -0.22), but the difference was statistically significant only for the 2800mg dose group.
Five patients (1.6%) in the LY-CoV555 group and nine patients (6.3%) in the placebo group were hospitalized or visited an emergency department by day 29, and one patient in the placebo group was admitted to ICU and there were no deaths.
Overall adverse effects were similar. No serious adverse effects were identified in the treatment group while one occurred in the placebo group. Mostly mild infusion-related reactions occurred in 2.3% of the treatment group and 1.4% of the placebo group. Viral variants resistant to Ly-CoV555 were found in 8.2% of participants in the monoclonal antibody group vs 6.1% of the placebo group, but the significance is unclear.
Comment: This is the first published study of monoclonal antibody treatment in outpatients with mild to moderate COVID-19 and demonstrates a decreased rate of hospitalization and ED visits. On November 9, 2020 the FDA issued an Emergency Use Authorization (EUA) for bamlanivimab (LY-CoV555) allowing its use for treatment of mild-moderate COVID-19 disease in children and adults ≥12 years and ≥ 40kg who are at high risk for severe disease.
Although there was a statistically significant difference in hospitalizations, the number of events were very few and risk factor stratification is sparse, and the dose recommended under the EUA (700 mg) was not proven to decrease viral load from baseline compared to placebo. It is interesting that hospitalizations and ED visits were combined as an endpoint, possibly because neither was statistically significant on its own. There was only one ICU admission and no deaths so we cannot make conclusions about prevention of critical disease. A parallel study (ACTIV-3) of this product in hospitalized patients was discontinued due to futility so, if efficacious, early timing of administration appears to be critical.
For those of us caring for children, the most concerning feature was that no patients aged 12-17 years were included. Further results from this ongoing study may help clarify questions of efficacy and safety, and the recent addition of pediatric patients to the study will provide valuable information about use in pediatrics.