Casirivimab and Imdevimab Treatment in Seropositive, Hospitalized COVID-19 Patients With Non-neutralizing or Borderline Neutralizing Antibodies

We conducted a post-hoc analysis in seropositive patients who were negative or borderline for functional neutralizing antibodies (nAbs) against SARS-CoV-2 at baseline from a phase 1/2/3 trial of casirivimab and imdevimab (CAS+IMD) treatment in hospitalized 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 nAb status. At baseline, 20.6% (178/864) of seropositive patients were negative/borderline for nAbs. CAS+IMD reduced viral load in patients who were negative/borderline for nAbs versus placebo, but not in patients who were positive for nAbs. We observed a trend in reduction of the proportion of patients who died or required mechanical ventilation (MV), as well as in all-cause mortality, by day 29 with CAS+IMD versus placebo in patients who were negative/borderline for nAbs. In those who were negative/borderline for nAbs, the proportions who died/needed MV from days 1-29 were 19.1% and 10.9%, and the proportions of patients who died from days 1-29 were 16.2% and 9.1%, in the placebo and CAS+IMD combined dose groups, respectively. No measurable harm or benefit in death/MV or all-cause mortality was observed in patients who were positive for nAbs. In hospitalized COVID-19 patients on low-flow or no supplemental oxygen, CAS+IMD reduced viral load, the risk of death or MV, and all-cause mortality in seropositive patients who were negative/borderline for nAbs. ImportanceThe 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, who have 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 nAbs (ie, those who were negative or borderline for nAbs) who may still benefit from CAS+IMD treatment if infected with a susceptible variant. Therefore, utilizing seronegativity status alone to guide treatment decisions for patients with COVID-19 may fail to identify seropositive patients who could benefit from anti-SARS-CoV-2 monoclonal antibody therapies which retain activity against circulating strains, depending on how effectively their endogenous antibodies neutralize SARS-CoV-2.

Repeat Subcutaneous Administration of REGEN-COV(R) in Adults is Well-Tolerated and Prevents the Occurrence of COVID-19

BackgroundData show that a single dose of casirivimab and imdevimab (REGEN-COV(R)) is effective in treating hospitalized individuals and outpatients with COVID-19 and in post-exposure prophylaxis. We present results from a phase 1, double-blind, placebo-controlled trial evaluating the safety, tolerability, and efficacy of repeat monthly doses of subcutaneous (SC) REGEN-COV in uninfected adult volunteers who were healthy or had chronic stable medical conditions. MethodsSubjects were randomized (3:1) to SC REGEN-COV 1200 mg or placebo dosed every 4 weeks for up to 6 doses. The primary and secondary endpoints evaluated the safety, pharmacokinetics, and immunogenicity of multiple-dose administration of REGEN-COV. Efficacy was evaluated by the incidence of COVID-19 or SARS-CoV-2 seroconversion. ResultsIn total, 969 subjects were treated. Repeat monthly dosing of SC REGEN-COV led to a 92.4% relative risk reduction in clinically-defined COVID-19 compared to 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 was low (<5% subjects). No grade [≥]3 injection-site reactions (ISRs) or hypersensitivity reactions were reported. A slightly higher percentage of subjects reported TEAEs with REGEN-COV (54.9%) than placebo (48.3%), due to ISRs (all grade 1-2). Serious adverse events were rare and occurred at similar percentages in the REGEN-COV and placebo groups. No deaths were reported in the 6-month treatment period. ConclusionsRepeated monthly administration of 1200 mg SC REGEN-COV was well-tolerated with low immunogenicity, and showed a substantial risk reduction in COVID-19 occurrence. (ClinicalTrials.gov identifier, NCT04519437)

Phase 2 dose-ranging study of the virologic efficacy and safety of the combination COVID-19 antibodies casirivimab and imdevimab in the outpatient setting

BackgroundThe monoclonal antibody combination casirivimab and imdevimab (REGEN-COV(R)) reduced viral load, hospitalisation, or death when administered 1:1 as an intravenous (IV) dose [≥]1200 mg in a phase 3 COVID-19 outpatient study. Availability of subcutaneous (SC) and/or lower IV doses should increase accessibility and/or drug supplies for patients. MethodsThis is a double-blind, placebo-controlled study of SARS-CoV-2-infected outpatients who were asymptomatic, or symptomatic but without risk factors for severe COVID-19. Patients were randomised to single IV dose (517 patients) of REGEN-COV 300, 600, 1200 or 2400 mg or placebo; or a single SC dose (286 patients) of REGEN-COV 600 or 1200 mg or placebo. The primary endpoint was time-weighted average daily change from baseline (TWACB) in viral load from day 1 (baseline) through day 7 in patients seronegative to SARS-CoV-2 at baseline. FindingsAll REGEN-COV treatments showed significant (p<0{middle dot}001 versus pooled placebo) virologic reduction through day 7. Least-squares mean differences in TWACB viral load for the treatments versus placebo ranged from -0{middle dot}56 to -0{middle dot}71 log10 copies/mL. Each REGEN-COV treatment showed significant (p<0{middle dot}001 versus pooled placebo) and similar virologic reduction through day 7. There were no safety concerns, dose-related safety findings, grade [≥]2 infusion related/hypersensitivity reactions, grade [≥]3 injection-site reactions, nor fatalities. Two serious adverse events not related to COVID-19 or the study drug were reported. InterpretationIn asymptomatic and low-risk symptomatic SARS-CoV-2-infected outpatients seronegative for antibodies against SARS-CoV-2 at baseline, REGEN-COV significantly and comparably reduced viral load at all IV and SC doses. FundingRegeneron Pharmaceuticals, Inc. and Hoffman-La Roche RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSEarly phase 1/2 data in coronavirus disease 2019 (COVID-19) outpatients (NCT04425629) found that the REGEN-COV(R) antibody combination, casirivimab and imdevimab, administered 1:1 as a single intravenous (IV) dose of 2400 mg or 8000 mg significantly reduced viral load over the first week compared to placebo. Enhanced viral clearance was more pronounced in patients who were seronegative for antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or who had high viral load at baseline. The phase 3 portion of this outpatient treatment study subsequently evaluated 1200 mg IV and 2400 mg IV doses, demonstrating consistent virologic efficacy, further demonstrating that REGEN-COV treatment reduced risk of COVID-19-related hospitalisation or all-cause death, and shortened time to symptom resolution. Virologic clearance was similar among those treated with any of the three doses (8000 mg, 2400 mg, or 1200 mg); therefore, maximal virologic efficacy may have been achieved at the 1200 mg dose in this treatment setting. These results warranted investigation of lower dose regimens. Added value of this studyThe present dose-ranging study evaluated whether a lower dose regimen could demonstrate virologic efficacy similar to that observed with 1200 mg IV and 2400 mg IV doses in outpatient treatment study. Exploration of a wider dose range will provide further characterisation of the clinical effects of REGEN-COV. Moreover, identifying a lower efficacious dose could bolster the ability to provide an adequate therapeutic supply of REGEN-COV in the setting of a global pandemic. A 1200 mg subcutaneous (SC) dose of REGEN-COV also prevented COVID-19 in household contacts of SARS-CoV-2-infected individuals (NCT04452318). The availability of a SC regimen could improve access for patients who have confirmed SARS-CoV-2 infection but for who IV infusion is not feasible. Implications of all the available evidenceDespite the growing number of therapeutics with authorisation or approval for the treatment and/or prevention of COVID-19, there remains a significant global need for effective COVID-19 therapies. Additional therapeutics and dosing regimens will be required to meet demand and to meet the needs of specific patient populations. Lower IV doses of REGEN-COV, and the option of SC administration, should increase accessibility for patients. This increased availability needs to be weighed against several unanswered questions, including 1) whether the correlation between decreased viral load in the nasopharynx and improvement in clinical outcome holds at lower doses of REGEN-COV, and 2) whether the reduced drug exposure margins are sufficient to prevent viral escape and emergence of variants of concern.

REGEN-COV for the Treatment of Hospitalized Patients with Covid-19

BackgroundHospitalized patients with COVID-19 experience high mortality rates, ranging from 10% to 30%. Combined casirivimab and imdevimab (CAS+IMD) is authorized for use in outpatients with COVID-19 and in post-exposure prophylaxis. The UK-based platform RECOVERY study reported improved survival in hospitalized seronegative patients treated with CAS+IMD; however, in most of the world, anti-spike monoclonal antibody therapy is currently not approved for hospitalized patients. MethodsIn this phase I/II/III double-blind placebo-controlled trial, patients hospitalized with COVID-19 were randomized (1:1:1) to 2.4 g or 8.0 g of CAS+IMD or placebo, and characterized at baseline for viral load and SARS-CoV-2 endogenous immune response. Results1336 patients on low-flow or no supplemental oxygen were treated. The primary endpoint was met: in seronegative patients, the least squares mean difference (CAS+IMD vs placebo) for time-weighted average change from baseline viral load was -0.28 log10 copies/mL (95% confidence interval [CI] -0.51 to -0.05; P = .0172). The primary clinical analysis of death or mechanical ventilation from day 6 to 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; nominal P = .0032). No safety concerns were noted. ConclusionsIn hospitalized patients with COVID-19 on low-flow or no oxygen, CAS+IMD treatment reduced viral load and the risk of death or mechanical ventilation as well as all-cause mortality in the overall population, with the benefit driven by seronegative patients and no harm observed in seropositive patients.

REGEN-COV Antibody Cocktail in Outpatients with Covid-19

BackgroundContinued SARS-CoV-2 infections and COVID-19-related hospitalizations highlight the need for effective anti-viral treatments in the outpatient setting. In a descriptive interim analysis of the phase 1/2 portion of a double-blind phase 1/2/3 trial in COVID-19 outpatients conducted between June 16, 2020 and September 4, 2020, REGEN-COV(R) (casirivimab plus imdevimab) antibody combination reduced SARS-CoV-2 viral load versus placebo. MethodsThis final phase 1/2 analysis comprises 799 outpatients, including 275 from the previous descriptive analysis (group-1) and 524 from phase 2 (group-2). Patients were randomized (1:1:1) to placebo, REGEN-COV 2400mg, or REGEN-COV 8000mg. Prespecified hierarchical analyses of virologic endpoints were performed in group-2. The proportion of patients with [≥]1 COVID-19-related medically attended visit (MAV) through day 29 was assessed in group-1+2. Efficacy was assessed in patients confirmed SARS-CoV-2-positive by baseline nasopharyngeal RT-qPCR. Safety was assessed in all treated patients. ResultsData from 799 outpatients enrolled from June 16, 2020 to September 23, 2020 are reported. Time-weighted average daily reduction in viral load through day 7 was significantly greater in the REGEN-COV combined 2400mg+8000mg group versus placebo in patients with baseline viral load >107 copies/mL (prespecified primary endpoint): -0.68 log10 copies/ml (95% CI, -0.94 to -0.41; P<.0001). This reduction was - 0.73 (P<.0001) and -0.36 (P=.0003) log10 copies/mL in serum antibody-negative patients and in the overall population, respectively. REGEN-COV reduced the proportion of patients with [≥]1 COVID-19-related MAV versus placebo (2.8% [12/434] REGEN-COV combined dose group versus 6.5% [15/231] placebo; P=.024; relative risk reduction [RRR]=57%); in patients with [≥]1 risk factor for hospitalization, the treatment effect was more pronounced (RRR=71%). Adverse events were similar across groups. ConclusionsIn COVID-19 outpatients enrolled prior to the widespread circulation of delta and omicron variants, treatment with REGEN-COV significantly reduced viral load and COVID-19-related MAVs.