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IMPORTANCEThe monoclonal antibody combination of casirivimab and imdevimab reduced viral load, hospitalization, or death when administered as a 1200-mg or greater intravenous (IV) dose in a phase 3 COVID-19 outpatient study. Subcutaneous (SC) and/or lower IV doses should increase accessibility and/or drug supplies for patients. OBJECTIVE To assess the virologic efficacy of casirivimab and imdevimab across different IV and SC doses compared with placebo. DESIGN, SETTING, AND PARTICIPANTS This phase 2, randomized, double-blind, placebocontrolled, parallel-group, dose-ranging study included outpatients with SARS-CoV-2 infection at 47 sites across the United States. Participants could be symptomatic or asymptomatic; symptomatic patients with risk factors for severe COVID-19 were excluded. Data were collected from December 15, 2020, to March 4, 2021. INTERVENTIONS Patients were randomized to a single IV dose (523 patients) of casirivimab and imdevimab at 300, 600, 1200, or 2400 mg or placebo; or a single SC dose (292 patients) of casirivimab and imdevimab at 600 or 1200 mg or placebo. MAIN OUTCOMES AND MEASURES The primary end point was the time-weighted average daily change from baseline (TWACB) in viral load from day 1 (baseline) through day 7 in patients seronegative for SARS-CoV-2 at baseline. RESULTS Among 815 randomized participants, 507 (282 randomized to IV treatment, 148 randomized to SC treatment, and 77 randomized to placebo) were seronegative at baseline and included in the primary efficacy analysis. Participants randomized to IV had a mean (SD) age of 34.6 (9.6) years (160 [44.6%] men; 14 [3.9%] Black; 121 [33.7%] Hispanic or Latino; 309 [86.1%] White); those randomized to SC had a mean age of 34.1 (10.0) years (102 [45.3%] men; 75 [34.7%] Hispanicor Latino; 6 [2.7%] Black; 190 [84.4%] White). All casirivimab and imdevimab treatments showed significant virologic reduction through day 7. Least-squares mean differences in TWACB viral load for casirivimab and imdevimab vs placebo ranged from -0.56 (95% CI; -0.89 to -0.24) log 10 copies/mL for the 1200-mg IV dose to -0.71 (95% CI, -1.05 to -0.38) log 10 copies/mL for the 2400-mg IV dose. There were no adverse safety signals or dose-related safety findings, grade 2 or greater infusionrelated or hypersensitivity reactions, grade 3 or greater injection-site reactions, or fatalities. Two serious adverse events not related to COVID-19 or the study drug were reported.

BackgroundPeramivir (PVR) is a potent neuraminidase inhibitor with in vitro activity against all influenza virus subtypes. Previous studies demonstrated the efficacy and safety of PVR as a single dose intravenous (IV) treatment for acute uncomplicated influenza in adults.MethodsA phase 3 study compared age-appropriate doses of single dose IV PVR to 5 days of oral oseltamivir (OSE) (4:1 randomization, stratified by age) in pediatric subjects age 0 -17 years within 48 hours of onset of acute uncomplicated influenza. Plasma concentrations of PVR were measured up to 6 hours post dose. Serial viral titers were measured from nasopharyngeal swabs. Severity of influenza signs and symptoms were recorded in a diary.Results122 subjects were enrolled up to a data cutoff of March 31, 2017 (<2 yrs, n = 7; 2-<7yrs, n = 37; 7-<13 yrs, n = 48; 13–17 yrs, n = 30). Interim results are reported for the first 108 subjects randomized, of which 101 (94%) received study drug. Influenza was confirmed by PCR in 75 (74%) subjects who received study drug (Intent-to-treat-Infected [ITTI] population). Key endpoints are summarized:PVROSEIntent to treat (ITT) population: n (all age groups)8523ITTI population: n (%)5916A/H1N122 (37%)9 (56%)A/H3N212 (20%)3 (19%)A/Ind1 (2%)0 (0%)B23 (39%)4 (25%)A + B1 (2%)0 (0%)Proportion of ITTI population shedding virus1, n (%)Baseline53/59 (90%)14/16 (88%)Day 327/59 (46%)10/16 (63%)Day 72/59 (3%)0/16 (0%)Day 140/59 (0%)0/16 (0%)Time to alleviation of symptoms, hrs275.6 (47.0, 109.2)99.8 (34.7, 133.6)Time to resolution of fever, hrs240.5 (22.1, 47.0)34.7 (13.7, 42.3) 1Determined by virus culture assay; 2ITTI population: median (95% CI).No serious adverse events were reported. AEs occurring in more than two subjects overall were:PVROSESafety population: n7823Any event17 (22%)5 (22%)Vomiting2 (3%)2 (9%)Nausea0 (0%)2 (9%)Pyrexia2 (3%)0 (0%)Tympanic membrane hyperemia2 (3%)0 (0%)ConclusionTreatment of influenza in pediatric subjects with single dose IV PVR or 5 days of oral OSE was generally safe and well tolerated. Whilst not powered for efficacy differences, trends were observed in more rapid reduction in virus shedding and symptom alleviation for PVR treated subjects compared with OSE. The study continues to enroll subjects < 7 years.Disclosures J. Vanchiere, BioCryst Pharmaceuticals: Consultant and Investigator, Consulting fee and Research support; S. Plunkett, BioCryst Pharmaceuticals: Investigator, Research support; R. Annamalai, BioCryst Pharmaceuticals: Investigator, Research support; K. Julien, BioCryst Pharmaceuticals: Investigator, Research support; J. Peterson, BioCryst Pharmaceuticals: Investigator, Research support; M. Goisse, BioCryst Pharmaceuticals: Investigator, Research support; S. Christensen, BioCryst Pharmaceuticals: Investigator, Research support; P. Mehta, BioCryst Pharmaceuticals: Investigator, Research support; S. Coleman, BioCryst Pharmaceuticals: Investigator, Research support; F. Munoz, BioCryst Pharmaceuticals: Investigator, Research support; A. Flynt, BioCryst Pharmaceuticals: ...