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

Trial Population

Screening, Randomization, Treatment, and Analysis.

In the original phase 3 portion of the trial, Regeneron requested that 2, 1, and 5 patients in the placebo, REGEN-COV 2400-mg, and REGEN-COV 8000-mg groups, respectively, withdraw from the trial because these patients underwent randomization in error. In the amended phase 3 portion of the trial, Regeneron requested that 2, 4, and 2 patients in the placebo, REGEN-COV 1200-mg, and REGEN-COV 2400-mg groups, respectively, withdraw from the trial because these patients underwent randomization in error. The modified full analysis set included all patients who were confirmed by means of quantitative reverse-transcriptase–polymerase-chain-reaction testing at a central laboratory to be positive for severe acute respiratory syndrome coronavirus 2 at baseline and who had at least one risk factor for severe coronavirus disease 2019 (Covid-19).

Patients were enrolled between September 24, 2020, and January 17, 2021. Initially, in the original phase 3 portion of the trial, 3088 patients, with or without risk factors for severe Covid-19, were randomly assigned to receive a single intravenous dose of REGEN-COV (8000 mg or 2400 mg) or placebo. In the amended phase 3 portion of the trial, an additional 2519 patients with at least one risk factor for severe Covid-19 were randomly assigned to receive a single dose of REGEN-COV (2400 mg or 1200 mg) or placebo (Figure 1). The median follow-up was 45 days, and 96.6% of the patients had more than 28 days of follow-up.

Baseline Demographic and Clinical Characteristics of Patients in the Modified Full Analysis Set.

The primary efficacy population included patients with at least one risk factor for severe Covid-19 and a test for SARS-CoV-2 confirmed at a central laboratory to be positive at baseline (modified full analysis set) (Figure 1). Among the 4057 patients in the modified full analysis set, demographic and baseline medical characteristics were balanced between the REGEN-COV and placebo groups (Table 1, and Table S2). In the overall modified full analysis set, the median age was 50 years (interquartile range, 38 to 59), 14% were at least 65 years of age, 49% were men, and 35% were Hispanic; the most common risk factors were obesity (in 58%), age of 50 years or older (52%), and cardiovascular disease (36%). A total of 3% of the patients were immunocompromised (Table S3).

The median viral load on nasopharyngeal RT-PCR was 6.98 log10 copies per milliliter (range, 5.45 to 7.85), and the majority of patients (69%) were SARS-CoV-2 serum antibody–negative at baseline; the high median viral load and the lack of an endogenous immune response at baseline suggested that enrolled patients were in the early phase of infection. At randomization, the patients reported that they had had Covid-19 symptoms for a median of 3 days (interquartile range, 2 to 5). The nasopharyngeal viral load, serum antibody–negative status, and median duration of Covid-19 symptoms at randomization were similar across the trial groups. The demographic and baseline medical characteristics of the patients in the REGEN-COV (8000 mg) modified full analysis set and the concurrent placebo group are shown in Table S4.

Natural History of Covid-19 in Outpatients

Among the patients who received placebo, there was an association between the baseline viral load and Covid-19–related hospitalization or death from any cause. A total of 55 of 876 patients (6.3%) with a high baseline viral load (>106 copies per milliliter) were hospitalized or died, as compared with 6 of 457 patients (1.3%) with a lower viral load (≤106 copies per milliliter) (Table S5).

Patients in the placebo group who were serum antibody–negative at baseline had higher median viral loads at baseline than those who were serum antibody–positive (7.45 log10 copies per milliliter and 4.96 log10 copies per milliliter, respectively). It also took longer for the viral levels in patients in the placebo group who were serum antibody–negative at baseline to fall below the lower limit of quantification (Fig. S2).

Despite these population-level observations, the baseline serum antibody status of patients who received placebo was not predictive of subsequent Covid-19–related hospitalization or death from any cause, because the incidences of these outcomes were similar among patients who were serum antibody–negative and those who were serum antibody–positive (49 of 930 patients [5.3%] and 12 of 297 patients [4.0%], respectively). The finding that serum antibody–positive status did not have a predictive value with respect to the reduction in the incidences of hospitalization or death suggests that some patients had an ineffective immune response. For example, patients in the placebo group who were serum antibody–positive but still had disease progression leading to hospitalization or death had high viral loads at baseline and day 7, similar to those in the placebo group who were serum antibody–negative and were hospitalized or died (Table S6).

Efficacy

Primary End Point

Hierarchical End Points. Clinical Efficacy.

Panel A shows the percentage of patients who were hospitalized or died from any cause in the amended phase 3 portion of the trial. Panel B shows the percentage of patients who were hospitalized or died from any cause in the original and amended phase 3 portions of the trial combined. Panel C shows the time to resolution of symptoms in the amended phase 3 portion of the trial. The lower and upper confidence limits are shown.

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%; 95% confidence interval [CI], 51.7 to 82.9; 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%; 95% CI, 31.6 to 87.1; P=0.002) (Table 2, Figure 2A and 2B, and Table S7). Five deaths occurred during the efficacy assessment period, including one in the REGEN-COV 2400-mg group, one in the REGEN-COV 1200-mg group, and three in the placebo group. Similar decreases in Covid-19–related hospitalization or death from any cause were observed across subgroups, including in patients who were serum antibody–positive at baseline (Table 2, and Fig. S3). REGEN-COV was also associated with decreases in hospitalization for any cause or death from any cause (Table S8).

Key Secondary End Points

The between-group difference in the percentage of patients with Covid-19–related hospitalization or death from any cause was observed starting approximately 1 to 3 days after the patients received REGEN-COV or placebo (Figure 2A and 2B). After these first 1 to 3 days, 5 of 1351 patients in the REGEN-COV 2400-mg group (0.4%), 5 of 735 patients in the REGEN-COV 1200-mg group (0.7%), 46 of 1340 patients in the placebo group who underwent randomization concurrently with the REGEN-COV 2400-mg group (3.4%), and 18 of 748 patients in the placebo group who underwent randomization concurrently with the REGEN-COV 1200-mg group (2.4%) had Covid-19–related hospitalization or died (Table 2 and Fig. S4).

The median time to resolution of Covid-19 symptoms was 4 days shorter in both REGEN-COV dose groups than in the placebo groups (10 days vs. 14 days, respectively; P<0.001 each for 2400 mg and 1200 mg) (Table 2 and Figure 2C). The more rapid resolution of Covid-19 symptoms with either dose of REGEN-COV was evident by day 3. Both REGEN-COV doses were associated with similar improvements in resolution of symptoms across subgroups (Fig. S5).

Other Secondary End Points and Additional Analyses

The incidence of Covid-19–related hospitalization was lower among patients who received REGEN-COV than among those who received placebo (Table S9). Among patients who were hospitalized due to Covid-19, those in the REGEN-COV groups had shorter hospital stays and a lower incidence of admission to an intensive care unit (ICU) than those in the placebo groups (Table S10).

Covid-19–related hospitalization, emergency department visits, or death from any cause through day 29 occurred in fewer patients in the REGEN-COV groups than in the placebo groups (Table S11), and fewer patients in the REGEN-COV groups had worsening Covid-19 leading to any medically attended visit (hospitalization, an emergency department visit, a visit to an urgent care clinic or physician’s office, or a telemedicine visit) or death from any cause (Table S9). The clinical efficacy of REGEN-COV at a dose of 8000 mg is shown in Tables S12 and S13.

Fewer symptomatic patients without risk factors for severe Covid-19 had at least one Covid-19–related hospitalization or death from any cause in the REGEN-COV groups than in the placebo groups, although there were few hospitalizations or deaths overall (Table S14). In patients without risk factors, the time to resolution of symptoms was 2 or 3 days shorter in patients who received REGEN-COV than in those who received placebo. Collectively, these data indicate a potential benefit of REGEN-COV, regardless of the presence or absence of baseline risk factors for severe Covid-19.

All REGEN-COV dose levels led to similar and more rapid declines in the viral load than placebo. The least-squares mean difference between 1200 mg, 2400 mg, and 8000 mg of REGEN-COV and placebo in the viral load from baseline through day 7 was −0.71 log10 copies per milliliter (95% CI, −0.90 to −0.53), −0.86 log10 copies per milliliter (95% CI, −1.00 to −0.72), and −0.87 log10 copies per milliliter (95% CI, −1.07 to −0.67), respectively (Figs. S6 through S8).

Safety

Serious Adverse Events and Adverse Events of Special Interest in the Safety Population.

More patients had serious adverse events in the placebo group (4.0%) than in the three REGEN-COV groups (1.1 to 1.7%) (Table 3). More patients had adverse events that resulted in death in the placebo group (5 of 1843 patients [0.3%]) than in the REGEN-COV groups: 1 of 827 patients (0.1%) in the 1200-mg group, 1 of 1849 patients (<0.1%) in the 2400-mg group, and none of the 1012 patients in the 8000-mg group (Table 3 and Table S15). Most adverse events were consistent with complications of Covid-19 (Table S16), and the majority were not considered by the investigators to be related to the trial drug. Few patients had infusion-related reactions of grade 2 or higher (no patients in the placebo group; 2 patients in the 1200-mg group, 1 patient in the 2400-mg group, and 3 patients in the 8000-mg group) or hypersensitivity reactions (1 patient in the placebo group and 1 patient in the 2400-mg group) (Table 3). A similar safety profile was observed among the REGEN-COV doses, with no discernable imbalance in safety events.

Pharmacokinetics

The mean concentrations of casirivimab and imdevimab in serum increased in a dose-proportional manner and were consistent with linear pharmacokinetics for the single intravenous doses (Table S17). At the end of the infusion, the mean (±SD) concentrations of casirivimab and imdevimab in serum were 185±74.5 mg per liter and 192±78.9 mg per liter, respectively, with the REGEN-COV 1200-mg dose and 321±106 mg per liter and 321±112 mg per liter, respectively, with the REGEN-COV 2400-mg dose. At day 29, the mean concentrations of casirivimab and imdevimab in serum were 46.4±22.5 mg per liter and 38.3±19.6 mg per liter, respectively, with the REGEN-COV 1200-mg dose and 73.2±27.2 mg per liter and 60.0±22.9 mg per liter, respectively, with the REGEN-COV 2400-mg dose. The mean estimated half-life was 28.8 days for casirivimab and 25.5 days for imdevimab.

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