The new england journal of medicine oronavirus disease 2019 (Covid-19) the outpatient setting. We examined the effect of emerged in late 2019 and spread rapidly, the neutralizing antibody on viral load, symptom Cresulting in a global pandemic. Infected scores, and clinical outcomes and also report an persons can have a wide range of disease severity, observed connection between a persistently high with many patients showing mild or even asymp- viral load and disease severity. tomatic disease. However, for unknown reasons, up to 10% of asymptomatic and mild infections Methods lead to more severe outcomes, including respira- 1 Trial Design, Treatment, and Oversight tory distress requiring hospitalization. Although risk factors for more severe outcomes have been In this randomized, double-blind, placebo-con- described (including an older age, obesity, hyper- trolled, single-dose trial conducted at 41 centers tension, and underlying chronic medical condi- in the United States, all the patients had positive tions),2,3 the connection between viral load and results on testing for SARS-CoV-2 and presented outcomes has not previously been tested in a with one or more mild or moderate symptoms. longitudinal study. Several treatment options The investigators reviewed the symptoms, risk have been explored for hospitalized patients factors, and other inclusion and exclusion crite- 4 with Covid-19 (e.g., antimalarial drugs, antiviral ria before enrollment. (A full list of the inclusion 5-7 8-12 agents, immunomodulators, glucocorti- and exclusion criteria is provided in the protocol, 13,14 15,16 coids, and convalescent plasma ) with available with the full text of this article at varying results. However, there have been no NEJM.org.) Each patient received a single intra- large randomized, controlled trials of targeted venous infusion of LY-CoV555 or placebo mono- treatments that are specific for severe acute re- therapy over approximately 1 hour. Although spiratory syndrome coronavirus 2 (SARS-CoV-2) the trial contains additional treatment groups, and that are intended to attenuate disease pro- here we focus on the interim analysis of results gression in patients with early disease. from only four of these groups: LY-CoV555 at Preclinical studies of neutralizing-antibody doses of 700 mg, 2800 mg, and 7000 mg and treatments for SARS-CoV-2 infection in several placebo. (Clinical details are also provided in the animal models have shown promising results, protocol.) with marked reductions in viral loads in the up- The preplanned interim analysis was triggered 17 per and lower respiratory tracts. SARS-CoV-2 on September 5, 2020, when the last patient gains entry into cells through binding of its who was randomly assigned to receive LY-CoV555 spike protein to receptors for angiotensin-con- reached day 11. The analysis includes all the data 18 verting enzyme 2 on target cells. LY-CoV555 regarding virologic features and symptoms that (also known as LY3819253), a potent antispike were available at the time of the database lock. neutralizing monoclonal antibody that binds with The doses of LY-CoV555 that were evaluated in high affinity to the receptor-binding domain of this trial were based on pharmacologic model- SARS-CoV-2, was derived from convalescent plas- ing that predicted that the 700-mg dose would ma obtained from a patient with Covid-19. The be efficacious. (Details about dose selection are antibody was developed by Eli Lilly after its dis- provided in the Supplementary Appendix, avail- covery by researchers at AbCellera and at the able at NEJM.org.) Given the gravity of the pan- Vaccine Research Center of the National Institute demic, the doses that were administered in this of Allergy and Infectious Diseases. The discovery trial were increased by up to a factor of 10 over of LY-CoV555 and its passive protection against the predicted efficacious dose to ensure adequate SARS-CoV-2 in nonhuman primates has been target coverage. The use of these doses was sup- 19 reported previously. ported by safety data from a phase 1 trial of Here, we report interim results from the LY-CoV555 involving hospitalized patients. Dose Blocking Viral Attachment and Cell Entry with levels were fixed, and either LY-CoV555 or pla- SARS-CoV-2 Neutralizing Antibodies (BLAZE-1) cebo was administered within 3 days after posi- trial, an ongoing phase 2 trial to evaluate the tive results on SARS-CoV-2 testing. efficacy and safety of LY-CoV555 in patients with The trial, which was sponsored by Eli Lilly, recently diagnosed mild or moderate Covid-19 in was conducted in accordance with principles of 2 n engl j med nejm.org The New England Journal of Medicine Downloaded from nejm.org on November 19, 2020. For personal use only. No other uses without permission. Copyright © 2020 Massachusetts Medical Society. All rights reserved.