Casirivimab and Imdevimab for the Treatment of Hospitalized Patients With COVID-19.

BACKGROUND: The open-label RECOVERY study reported improved survival in hospitalized, SARS-CoV-2 seronegative patients treated with casirivimab and imdevimab (CAS + IMD). METHODS: In this phase I/II/III, double-blind, placebo-controlled trial conducted prior to widespread circulation of Delta and Omicron, hospitalized COVID-19 patients were randomized (1:1:1) to 2.4 g or 8.0 g CAS + IMD or placebo, and characterized at baseline for viral load and SARS-CoV-2 serostatus. RESULTS: 1336 patients on low-flow or no supplemental (low-flow/no) oxygen were treated. The primary endpoint was met: in seronegative patients, the least-squares mean difference (CAS + IMD versus placebo) for time-weighted average change from baseline in viral load through day 7 was -0.28 log10 copies/mL (95% CI, -0.51 to -0.05; P = .0172). The primary clinical analysis of death or mechanical ventilation (death/MV) from day 6-29 in patients with high viral load had a strong positive trend but did not reach significance. CAS + IMD numerically reduced all-cause mortality in seronegative patients through day 29 (relative risk reduction, 55.6%; 95% CI, 24.2-74.0). No safety concerns were noted. CONCLUSIONS: In hospitalized COVID-19 patients on low-flow/no oxygen, CAS + IMD reduced viral load and likely improves clinical outcomes in the overall population, with the benefit driven by seronegative patients, and no harm observed in seropositive patients.

Casirivimab and Imdevimab Treatment Reduces Viral Load and Improves Clinical Outcomes in Seropositive Hospitalized COVID-19 Patients with Nonneutralizing or Borderline Neutralizing Antibodies.

We conducted a post hoc analysis in seropositive patients who were negative or borderline for functional neutralizing antibodies (NAbs) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at baseline from a phase 1, 2, and 3 trial of casirivimab and imdevimab (CAS+IMD) treatment in hospitalized coronavirus disease 2019 (COVID-19) patients on low-flow or no supplemental oxygen prior to the emergence of Omicron-lineage variants. Patients were randomized to a single dose of 2.4 g CAS+IMD, 8.0 g CAS+IMD, or placebo. Patients seropositive for anti-SARS-CoV-2 antibodies at baseline were analyzed by their baseline neutralizing antibody status. At baseline, 20.6% (178/864) of seropositive patients were negative or borderline for neutralizing antibodies, indicating negative or very low functionally neutralizing anti-SARS-CoV-2 antibodies. CAS+IMD reduced viral load in patients who were negative or borderline for neutralizing antibodies versus placebo, but not in patients who were positive for neutralizing antibodies. In patients who were negative or borderline for neutralizing antibodies, we observed a trend in reduction of the proportion of patients who died or required mechanical ventilation, as well as in all-cause mortality, by day 29 with CAS+IMD versus placebo. The proportions of patients who died or required mechanical ventilation from days 1 to 29 were 19.1% in the placebo group and 10.9% in the CAS+IMD combined-dose group, and the proportions of patients who died (all-cause mortality) from days 1 to 29 were 16.2% in the placebo group and 9.1% in the CAS+IMD combined-dose group. In patients who were positive for neutralizing antibodies, no measurable harm or benefit was observed in either the proportion of patients who died or required mechanical ventilation or the proportion of patients who died (all-cause mortality). In hospitalized COVID-19 patients on low-flow or no supplemental oxygen, CAS+IMD reduced viral load, the risk of death or mechanical ventilation, and all-cause mortality in seropositive patients who were negative or borderline for neutralizing antibodies. IMPORTANCE The clinical benefit of CAS+IMD in hospitalized seronegative patients with COVID-19 has previously been demonstrated, although these studies observed no clinical benefit in seropositive patients. As the prevalence of SARS-CoV-2-seropositive individuals rises due to both vaccination and previous infection, it is important to understand whether there is a subset of hospitalized patients with COVID-19 with antibodies against SARS-CoV-2 who could benefit from anti-SARS-CoV-2 monoclonal antibody treatment. This post hoc analysis demonstrates that there is a subset of hospitalized seropositive patients with inadequate SARS-CoV-2-neutralizing antibodies (i.e., those who were negative or borderline for neutralizing antibodies) who may still benefit from CAS+IMD treatment if infected with a susceptible SARS-CoV-2 variant. Therefore, utilizing serostatus alone to guide treatment decisions for patients with COVID-19 may fail to identify those seropositive patients who could benefit from anti-SARS-CoV-2 monoclonal antibody therapies known to be effective against circulating strains, dependent upon how effectively their endogenous antibodies neutralize SARS-CoV-2.

Virologic Efficacy of Casirivimab and Imdevimab COVID-19 Antibody Combination in Outpatients With SARS-CoV-2 Infection: A Phase 2 Dose-Ranging Randomized Clinical Trial.

Importance: The 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, placebo-controlled, 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%] Hispanic or 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) log10 copies/mL for the 1200-mg IV dose to -0.71 (95% CI, -1.05 to -0.38) log10 copies/mL for the 2400-mg IV dose. There were no adverse safety signals or dose-related safety findings, grade 2 or greater infusion-related 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. Conclusions and Relevance: In this randomized clinical trial including outpatients with asymptomatic and low-risk symptomatic SARS-CoV-2, all IV and SC doses of casirivimab and imdevimab comparably reduced viral load. Trial Registration: ClinicalTrials.gov Identifier: NCT04666441.

Repeat subcutaneous administration of casirivimab and imdevimab in adults is well-tolerated and prevents the occurrence of COVID-19.

OBJECTIVES: A phase 1, double-blind, placebo-controlled trial was conducted to evaluate the safety, tolerability, and exploratory efficacy of repeat monthly doses of subcutaneous (SC) casirivimab and imdevimab (CAS+IMD) in uninfected adult volunteers. METHODS: Participants were randomized (3:1) to SC CAS+IMD 1200 mg or placebo every 4 weeks for up to six doses. Primary and secondary end points evaluated safety, pharmacokinetics, and immunogenicity. Exploratory efficacy was evaluated by the incidence of COVID-19 or SARS-CoV-2 seroconversion. RESULTS: In total, 969 participants received CAS+IMD. Repeat monthly dosing of SC CAS+IMD led to a 92.4% relative risk reduction in clinically defined COVID-19 compared with placebo (3/729 [0.4%] vs 13/240 [5.4%]; odds ratio 0.07 [95% CI 0.01-0.27]), and a 100% reduction in laboratory-confirmed COVID-19 (0/729 vs 10/240 [4.2%]; odds ratio 0.00). Development of anti-drug antibodies occurred in a small proportion of participants (<5%). No grade ≥3 injection-site reactions (ISRs) or hypersensitivity reactions were reported. Slightly more participants reported treatment-emergent adverse events with CAS+IMD (54.9%) than with placebo (48.3%), a finding that was due to grade 1-2 ISRs. Serious adverse events were rare. No deaths were reported in the 6-month treatment period. CONCLUSION: Repeat monthly administration of 1200 mg SC CAS+IMD was well-tolerated, demonstrated low immunogenicity, and showed a substantial risk reduction in COVID-19 occurrence.

REGEN-COV Antibody Combination and Outcomes in Outpatients with Covid-19.

BACKGROUND: In the phase 1-2 portion of an adaptive trial, REGEN-COV, a combination of the monoclonal antibodies casirivimab and imdevimab, reduced the viral load and number of medical visits in patients with coronavirus disease 2019 (Covid-19). REGEN-COV has activity in vitro against current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern. METHODS: In the phase 3 portion of an adaptive trial, we randomly assigned outpatients with Covid-19 and risk factors for severe disease to receive various doses of intravenous REGEN-COV or placebo. Patients were followed through day 29. A prespecified hierarchical analysis was used to assess the end points of hospitalization or death and the time to resolution of symptoms. Safety was also evaluated. RESULTS: Covid-19-related hospitalization or death from any cause occurred in 18 of 1355 patients in the REGEN-COV 2400-mg group (1.3%) and in 62 of 1341 patients in the placebo group who underwent randomization concurrently (4.6%) (relative risk reduction [1 minus the relative risk], 71.3%; P<0.001); these outcomes occurred in 7 of 736 patients in the REGEN-COV 1200-mg group (1.0%) and in 24 of 748 patients in the placebo group who underwent randomization concurrently (3.2%) (relative risk reduction, 70.4%; P = 0.002). The median time to resolution of symptoms was 4 days shorter with each REGEN-COV dose than with placebo (10 days vs. 14 days; P<0.001 for both comparisons). REGEN-COV was efficacious across various subgroups, including patients who were SARS-CoV-2 serum antibody-positive at baseline. Both REGEN-COV doses reduced viral load faster than placebo; the least-squares mean difference in viral load from baseline through day 7 was -0.71 log10 copies per milliliter (95% confidence interval [CI], -0.90 to -0.53) in the 1200-mg group and -0.86 log10 copies per milliliter (95% CI, -1.00 to -0.72) in the 2400-mg group. Serious adverse events occurred more frequently in the placebo group (4.0%) than in the 1200-mg group (1.1%) and the 2400-mg group (1.3%); infusion-related reactions of grade 2 or higher occurred in less than 0.3% of the patients in all groups. CONCLUSIONS: REGEN-COV reduced the risk of Covid-19-related hospitalization or death from any cause, and it resolved symptoms and reduced the SARS-CoV-2 viral load more rapidly than placebo. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT04425629.).

Successful Clearance of 300 Day SARS-CoV-2 Infection in a Subject with B-Cell Depletion Associated Prolonged (B-DEAP) COVID by REGEN-COV Anti-Spike Monoclonal Antibody Cocktail.

A 59-year-old male with follicular lymphoma treated by anti-CD20-mediated B-cell depletion and ablative chemotherapy was hospitalized with a COVID-19 infection. Although the patient did not develop specific humoral immunity, he had a mild clinical course overall. The failure of all therapeutic options allowed infection to persist nearly 300 days with active accumulation of SARS-CoV-2 virus mutations. As a rescue therapy, an infusion of REGEN-COV (10933 and 10987) anti-spike monoclonal antibodies was performed 270 days from initial diagnosis. Due to partial clearance after the first dose (2.4 g), a consolidation dose (8 g) was infused six weeks later. Complete virus clearance could then be observed over the following month, after he was vaccinated with the Pfizer-BioNTech anti-COVID-19 vaccination. The successful management of this patient required prolonged enhanced quarantine, monitoring of virus mutations, pioneering clinical decisions based upon close consultation, and the coordination of multidisciplinary experts in virology, immunology, pharmacology, input from REGN, the FDA, the IRB, the health care team, the patient, and the patient's family. Current decisions to take revolve around patient's follicular lymphoma management, and monitoring for virus clearance persistence beyond disappearance of REGEN-COV monoclonal antibodies after anti-SARS-CoV-2 vaccination. Overall, specific guidelines for similar cases should be established.

A Retrospective Study of COVID-19-Related Urgent Medical Visits and Hospitalizations After Outpatient COVID-19 Diagnosis in the US.

INTRODUCTION: Identifying risk factors for progression to severe COVID-19 requiring urgent medical visits and hospitalizations (UMVs) among patients initially diagnosed in the outpatient setting may help inform patient management. The objective of this study was to estimate the incidence of and risk factors for COVID-19-related UMVs after outpatient COVID-19 diagnosis or positive SARS-CoV-2 test. METHODS: Data for this retrospective cohort study were from the Optum® de-identified COVID-19 Electronic Health Record database from June 1 to December 9, 2020. Adults with first COVID-19 diagnosis or positive SARS-CoV-2 test in outpatient settings were identified. Cumulative incidence function analysis stratified by risk factors was used to estimate the 30-day incidence of COVID-19-related UMVs. Competing risk regression models were used to derive adjusted hazard ratios (aHR) and 95% confidence intervals (95% CI) for factors associated with UMVs. RESULTS: Among 206,741 patients [58.8% female, 77.5% non-Hispanic Caucasian, mean (SD) age: 46.7 (17.8) years], the 30-day incidence was 9.4% (95% CI 9.3-9.6) for COVID-19-related emergency room (ER)/urgent care (UC)/hospitalizations and 3.8% (95% CI 3.7-3.9) for COVID-19-related hospitalizations. Likelihood of hospitalization increased with age and body mass index, with age the strongest risk factor (aHR 5.61; 95% CI 4.90-6.32 for patients ≥ 85 years). Increased likelihood of hospitalization was observed for first presentation in the ER/UC vs. non-ER/UC outpatient settings (aHR 2.35; 95% CI 2.22-2.47) and prior all-cause hospitalization (aHR 1.90; 95% CI 1.79-2.00). Clinical risk factors of hospitalizations included pregnancy, uncontrolled diabetes, chronic obstructive pulmonary disease, chronic kidney disease, and autoimmune disease. A study limitation is that data on COVID-19 severity and symptoms were not captured. CONCLUSION: Predictors of COVID-19-related UMVs include older age, obesity, and several comorbidities. These findings may inform patient management and resource allocation following outpatient COVID-19 diagnosis.