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The
new england journal
of
medicine
n engl j med nejm.org
1
The authors’ full names, academic de -
grees, and af filiations are listed in the
Appen dix. Dr. Weinreich can be contac ted
at david.weinreich@regeneron.com or at
Regeneron Pharmaceuticals, 777 Old Saw
Mill River Rd., Tarrytown, NY 10591-6707.
*A complete list of the trial investigators
is provided in the Supplementary Ap-
pendix, available at NEJM.org.
This article was published on September
29, 2021, at NEJM.org.
DOI: 10.1056/NEJMoa2108163
Copyright © 2021 Massachusetts Medical Society.
BAC KGRO UND
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. Safet y was also evaluated.
RE SULT S
Covid-19–related hospitalization or death from any cause occurred in 18 of 1355 pa-
tients 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 reduc-
tion [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 reduc-
tion, 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, in-
cluding 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 log
10
copies per
milliliter (95% confidence interval [CI], −0.90 to −0.53) in the 1200-mg group and
−0.86 log
10
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 reac-
tions 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 rap-
idly than placebo. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials
.gov number, NCT04425629.)
ABS TR AC T
REGEN-COV Antibody Combination
and Outcomes in Outpatients with Covid-19
D.M. Weinreich, S. Sivapalasingam, T. Norton, S. Ali, H. Gao, R. Bhore, J. Xiao,
A.T. Hooper, J.D. Hamilton, B.J. Musser, D. Rofail, M. Hussein, J. Im,
D.Y. Atmodjo, C. Perry, C. Pan, A. Mahmood, R. Hosain, J.D. Davis, K.C. Turner,
A. Baum, C.A. Kyratsous, Y. Kim, A. Cook, W. Kampman, L. Roque-Guerrero,
G. Acloque, H. Aazami, K. Cannon, J.A. Simón-Campos, J.A. Bocchini, B. Kowal,
A.T. DiCioccio, Y. Soo, G.P. Geba, N. Stahl, L. Lipsich, N. Braunstein, G. Herman,
and G.D. Yancopoulos, for the Trial Investigators*
Origina l A rt icl e
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The
new england journal
of
medicine
S
ev ere acu te r espir a tor y sy ndrome
coronavirus 2 (SARS-CoV-2) causes corona-
virus disease 2019 (Covid-19), and as of
September 2021, it has infected more than 230
million people and led to approximately 4.7 mil-
lion deaths globally.
1
Although most patients
with Covid-19 receive care in the outpatient set-
ting, some have disease that progresses to severe
illness leading to hospitalization or death.
2-6
Sev-
eral investigational therapeutic agents, including
REGEN-COV (previously known as REGN-COV2),
are available under emergency use authorization.
However, there have been limited clinical data to
support their wider use and no approved treat-
ments to reduce the risk of hospitalization or
death among patients with mild-to-moderate
Covid-19. There is also a need for therapeutic
agents that remain effective against emerging
SARS-CoV-2 variants of concern, which contain
mutations that attenuate immunity resulting from
previous SARS-CoV-2 infection, vaccination, and
some monoclonal antibodies.
7-10
To develop a therapeutic agent that would
retain activity against emerging variants, high-
throughput screening was undertaken to generate
an antibody cocktail consisting of two SARS-CoV-2
neutralizing antibodies against distinct, non-
overlapping epitopes on the spike protein.
11-1 3
In
vitro studies showed that this antibody cocktail,
REGEN-COV, retains activity against current
variants of concern and variants of interest, in-
cluding B.1.1.7 (or alpha), B.1.429 (or epsilon),
B.1.617.2 (or delta), and E484K-containing variants
such as B.1.351 (or beta), P.1 (or gamma), and
B.1.526 (or iota).
9,14
In the phase 1–2 portion of
this phase 1–3 adaptive, multicenter, double-blind,
randomized, placebo-controlled trial, REGEN-COV
was eff icacious in symptomatic outpatients, in
whom it reduced the SARS-CoV-2 viral load
and the need for medical attention related to
Covid-1 9.
15,16
Here, we report the results of the
primary analysis of the phase 3 portion of this
trial.
Methods
Trial Design and Oversight
The phase 3 portion of this trial involving outpa-
tients with Covid-19 comprised cohort 1 (patients
who were ≥18 years of age), cohort 2 (those who
were <18 years of age), and cohort 3 (those who
were pregnant at randomization). Initially, the
patients were randomly assigned in a 1:1:1 ratio
to receive intravenous REGEN-COV at a dose of
2400 mg (1200 mg each of casirivimab and im-
devimab) or 8000 mg (4000 mg of each anti-
body) or intravenous placebo (Fig. S1 in the
Supplementary Appendix, available with the full
text of this article at NEJM.org).
On the basis of results of the phase 1–2 por-
tion of the trial, which showed that the 2400-mg
and 8000-mg doses had similar antiviral and
clinical efficacy and that most clinical events
occurred in high-risk patients,
15
the trial was
amended on November 14, 2020, so that patients
who were subsequently enrolled had at least one
risk factor for severe Covid-19 and were randomly
assigned in a 1:1:1 ratio to receive intravenous
REGEN-COV at a dose of 1200 mg (600 mg of
each antibody) or 2400 mg (1200 mg of each
antibody) or intravenous placebo. On February
25, 2021, on the basis of a recommendation
from an independent data and safet y monitoring
committee, patients were no longer randomly
assigned to receive placebo. The phase 3 primary
eff icacy analysis presented here involved cohort
1 patients who were assigned to receive either
2400 mg or 1200 mg of REGEN-COV, with their
concurrent placebo groups serving as a control;
the trial involving cohorts 2 and 3 is ongoing.
Regeneron designed the trial; gathered the
data, together with the trial investigators; and
analyzed the data. An independent data and
safety monitoring committee reviewed unblind-
ed data to make recommendations about trial
modif ication and termination.
The trial was conducted in accordance with
the principles of the Declaration of Helsinki,
International Council for Harmonisation Good
Clinical Practice guidelines, and all applicable
regulatory requirements. The local institutional
review board or ethics committee at each trial
center oversaw trial conduct and documentation.
All the patients provided written informed con-
sent before participating in the trial. Additional
details are provided in the Supplementary Meth-
ods section in the Supplementary Appendix.
Patients
Eligible patients in cohort 1 were 18 years of age
or older and were not hospitalized. These patients
had a confirmed local SARS-CoV-2–positive diag-
nostic test result no more than 72 hours before
randomization, with the onset of any Covid-19
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3
REGEN-COV Antibody Combination for Covid-19
symptom, as determined by the investigator, oc-
curring no more than 7 days before randomiza-
tion. Randomization into the initial phase 3
portion of the trial was stratified according to
country and the presence of risk factors for se-
vere Covid-19. In the amended phase 3 portion
of the trial, only patients with at least one risk
factor for severe Covid-19 were eligible. The full
list of inclusion and exclusion criteria is provided
in the protocol, available at NEJM.org.
All the patients were assessed at baseline for
anti–SARS-CoV-2 antibodies — anti-spike (S1)
IgA, anti-spike (S1) IgG, and anti-nucleocapsid
IgG — and were categorized for the analyses as
serum antibody–negative (if all available test
results were negative), serum antibody–positive
(if any available test result was positive), or other
(inconclusive or unknown results).
Intervention and A ssessment s
At baseline (day 1), REGEN-COV (diluted in
normal saline solution) or saline placebo was
administered intravenously. The solutions were
indistinguishable and were prepared by qualif ied
personnel who were not associated with the con-
duct of the trial. Hospitalizations were assessed
to be related to Covid-19 by the investigator. The
23-item Symptoms Evolution of COVID-19 in-
strument, an electronic diary, was used to assess
Covid-19 symptoms daily.
17
Quantitative viro-
logic analysis of nasopharyngeal swab samples
and serum antibody testing, as previously de-
scribed, were conducted in a central laboratory.
16
End Po ints
The primary and two key secondary end points
were tested hierarchically (Table S1). The primary
end point was the percentage of patients with
at least one Covid-19–related hospitalization or
death from any cause through day 29. The key
secondary clinical end points were the percent-
age of patients with at least one Covid-19–related
hospitalization or death from any cause from
day 4 through day 29 and the time to resolution
of Covid-19 symptoms (details are provided in
the Supplementary Methods section). For the
end point of resolution of symptoms, data on 19
of the 23 symptoms recorded were analyzed.
Data on targeted adverse events were collected
in this trial. The safety end points consisted of
serious adverse events and adverse events of spe-
cial interest (i.e., hypersensitivity events of grade
2 or higher, infusion-related reactions, and ad-
verse events for which medical attention at a
health care facility was warranted).
Statistical Analysis
The statistical analysis plan for the current analy-
sis (available with the protocol) was f inalized
before database lock and unblinding in the
phase 3 cohort 1; the primary analysis did not
include patients from the previously reported
phase 1–2 portion of the trial.
15,16
The full
analysis set included all symptomatic patients
who underwent randomization. As prespecif ied
in the statistical analysis plan, eff icacy analyses
were performed in a modified full analysis set,
defined as all patients who were confirmed by
means of quantitative reverse-transcriptase–poly-
merase-chain-reaction (RT-PCR) testing at a cen-
tral laboratory to be positive for SARS-CoV-2 at
baseline and who had at least one risk factor for
severe Covid-19. Additional analyses involved pa-
tients without risk factors for severe Covid-19.
Safety was assessed in patients in the full analysis
set who received REGEN-COV or placebo.
The percentage of patients with at least one
Covid-19–related hospitalization or death from
any cause was compared between each dose
group and concurrent placebo group with the
use of the stratif ied Cochran–Mantel–Haenszel
test, with countr y as a stratif ication factor. P val-
ues from the stratified Cochran–Mantel–Haenszel
test and 95% confidence intervals for relative
risk reduction were calculated with the Farring-
ton–Manning method.
18
The time to resolution
of Covid-19 symptoms was assessed in patients
with a baseline total severity score of more than
3 (on a scale from 0 to 38, with higher scores
indicating an increased burden of symptoms)
and analyzed with the use of the stratified log-
rank test, with country as a stratification factor.
Median times and associated 95% conf idence
intervals were derived with the use of the Kap-
lan–Meier method. The hazard ratios and 95%
confidence intervals were estimated with the use
of the Cox regression model.
Analyses of the primary and key secondary
end points were conducted at a two-sided alpha
level of 0.05 with the use of a hierarchical testing
strateg y to control for type I error. For the re-
porting of other secondary end points and analy-
ses, the widths of the conf idence inter vals were
not adjusted for multiplicity. Statistical analyses
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The
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were performed with SAS soft ware, version 9.4
(SAS Institute). Additional statistical methods
are described in the statistical analysis plan.
Resu lts
Trial Population
Patients were enrolled between September 24,
2020, and January 17, 2021. Initially, in the origi-
nal phase 3 portion of the trial, 3088 patients,
with or without risk factors for severe Covid-19,
were randomly assigned to receive a single intra-
venous 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
(Fig. 1). The median follow-up was 45 days, and
96.6% of the patients had more than 28 days of
follow-up.
The primary eff icacy population included
patients with at least one risk factor for severe
Covid-19 and a test for SARS-CoV-2 conf irmed at
a central laboratory to be positive at baseline
(modified full analysis set) (Fig. 1). Among the
4057 patients in the modif ied full analysis set,
demographic and baseline medical characteris-
tics were balanced between the REGEN-COV
and placebo groups (Table 1, and Table S2). In
the overall modif ied full analysis set, the medi-
an 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 immu-
nocompromised (Table S3).
The median viral load on nasopharyngeal
RT-PCR was 6.98 log
10
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 pa-
tients reported that they had had Covid-19 symp-
toms 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 demograph-
ic 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 (>10
6
copies
per milliliter) were hospitalized or died, as com-
pared with 6 of 457 patients (1.3%) with a lower
viral load (≤10
6
copies per milliliter) (Table S5).
Patients in the placebo group who were se-
rum antibody–negative at baseline had higher
median viral loads at baseline than those who
were serum antibody–positive (7.45 log
10
copies
per milliliter and 4.96 log
10
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 subse-
quent 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 se-
rum 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
Figure 1 (facing page). 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 80 00 -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 240 0-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 laborator y
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).
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REGEN-COV Antibody Combination for Covid-19
5607 Underwent randomization in phase 3, cohort 1
6716 Symptomatic patients were assessed for eligibility 306 Were excluded
259 Were excluded at screening
28 Had other reason
17 Declined to participate
1 Had adverse event
1 Was lost to follow-up
799 Underwent randomization in phase 1 or 2
5 Underwent randomization in phase 3, cohort 3
2519 Underwent randomization in the amended phase 3 portion of the trial
(patients had ≥1 risk factors for severe Covid-19)
3088 Underwent randomization in the original phase 3 portion of the trial
(patients had no risk factors or ≥1 risk factors for severe Covid-19)
660 With ≥1 risk factors for
severe Covid-19 were
assigned to receive placebo
688 With ≥1 risk factors for
severe Covid-19 were assigned
to receive REGEN-COV,
2400 mg
700 With ≥1 risk factors for
severe Covid-19 were assigned
to receive REGEN-COV,
8000 mg
1040 With no risk factors for
severe Covid-19 were excluded
840 Were assigned to
receive placebo
838 Were assigned to
receive REGEN-COV,
1200 mg
841 Were assigned to
receive REGEN-COV,
2400 mg
648 Received placebo
12 Did not receive placebo
680 Received REGEN-COV
8 Did not receive
REGEN-COV
619 Were included in the
modified full analysis set
748 Were included in the
modified full analysis set
736 Were included in the
modified full analysis set
736 Were included in the
modified full analysis set
625 Were included in the
modified full analysis set
593 Were included in the
modified full analysis set
1341 Were included in the
modified full analysis set
1355 Were included in the
modified full analysis set
689 Received REGEN-COV
11 Did not receive
REGEN-COV
423 Completed the trial
192 Are currently in
ongoing trial
45 Discontinued trial
16 Withdrew
15 Were lost to follow-up
4 Were withdrawn by
sponsor
4 Were withdrawn by
physician
3 Had adverse event
3 Died
455 Completed the trial
207 Are currently in
ongoing trial
26 Discontinued trial
13 Withdrew
10 Were lost to follow-up
2 Were withdrawn by
sponsor
1 Had adverse event
447 Completed the trial
219 Are currently in
ongoing trial
34 Discontinued trial
14 Withdrew
11 Were lost to follow-up
7 Were withdrawn by
sponsor
1 Was withdrawn by
physician
1 Had adverse event
0 Completed the trial
817 Are currently in
ongoing trial
23 Discontinued trial
15 Withdrew
4 Were lost to follow-up
2 Were withdrawn by
sponsor
1 Had adverse event
1 Had lack of efficacy
0 Completed the trial
819 Are currently in
ongoing trial
19 Discontinued trial
12 Withdrew
1 Was lost to follow-up
4 Were withdrawn by
sponsor
1 Was withdrawn by
physician
1 Died
0 Completed the trial
822 Are currently in
ongoing trial
19 Discontinued trial
11 Withdrew
3 Were lost to follow-up
2 Were withdrawn by
sponsor
2 Were withdrawn by
physician
1 Died
828 Received placebo
12 Did not receive placebo
827 Received REGEN-COV
11 Did not receive
REGEN-COV
832 Received REGEN-COV
9 Did not receive
REGEN-COV
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death suggests that some patients had an inef-
fective 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–nega-
tive and were hospitalized or died (Table S6).
Efficac y
Primary End Point
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 under-
went randomization concurrently (4.6%) (relative
risk reduction [1 minus the relative risk], 71.3%;
Table 1. Baseline Demographic and Clinical Characteristics of Patients in the Modified Full Analysis Set.*
Characteristic
REGEN-COV
2400 mg
(N = 1355)
Placebo
2400 mg
(N = 1341)†
REGEN-COV
1200 mg
(N = 736)
Placebo
1200 mg
N = 748)
Median age (IQR) — yr 50.0 (39.0–60.0) 50.0 (37.0–58.0) 48.5 (37.0–57.5) 48.0 (35.0–57.0)
Male sex — no. (%) 656 (48.4) 633 (47.2) 364 (49.5) 352 (47.1)
Race or ethnic group — no. (%)‡
White 1161 (85.7) 1136 (84.7) 595 (80.8) 611 (81.7)
Black 67 (4.9) 66 (4.9) 38 (5.2) 38 (5.1)
Asian 52 (3.8) 56 (4.2) 38 (5.2) 36 (4.8)
Hispanic or Latinx 464 (34.2) 471 (35.1) 312 (42.4) 295 (39.4)
American Indian or Alaska Native 19 (1.4) 13 (1.0) 17 (2.3) 10 (1.3)
Unknown 28 (2.1) 43 (3.2) 36 (4.9) 37 (4.9)
Not reported 24 (1.8) 26 (1.9) 10 (1.4) 15 (2.0)
Body-mass index§ 31.09±6.33 31.19±6.63 31.54±7.31 31.07±6.46
Obesity — no. (%)¶ 787 (58.1) 772 (57.6) 410 (55.7) 427 (57.1)
Viral load in nasopharyngeal swab
No. of patients 1353 1333 734 744
Median viral load (range) — log
10
copies/ml 7.01 (2.6–10.0) 6.95 (2.6–10.2) 6.92 (2.6–10.5) 6.85 (2.6–10.2)
Serum C-reactive protein level
No. of patients 1242 1243 713 724
Median level (range) — mg/liter 4.615
(0.11–354.16)
4.940
(0.10–242.73)
4.910
(0.11–238.53)
4.865
(0.16–227.45)
Serum antibody status — no. (%)
Negative 940 (69.4) 930 (69.4) 500 (67.9) 519 (69.4)
Positive 323 (23.8) 297 (22.1) 177 (24.0) 164 (21.9)
Other 92 (6.8) 114 (8.5) 59 (8.0) 65 (8.7)
Median time from symptom onset to randomization
(IQR) — days
3.0 (2–5) 3.0 (2–5) 3.0 (2–5) 3.0 (2–4)
* Plus–minus values are means ±SD. 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). Risk factors for severe Covid-19 include an
age of more than 50 years, obesity, cardiovascular disease (including hypertension), chronic lung disease (including asthma), chronic meta-
bolic disease (including diabetes), chronic kidney disease (including receipt of dialysis), chronic liver disease, and an immunocompromised
condition (immunosuppression or receipt of immunosuppressants). Percentages may not total 100 because of rounding. IQR denotes inter-
quartile range.
† The placebo group of 1341 patients who underwent randomization concurrently with the group that received 2400 mg of REGEN-COV included
the placebo group of 748 patients who underwent randomization concurrently with the group that received 1200 mg of REGEN-COV.
‡ Race and ethnic group were reported by the patients.
§ The body-mass index is the weight in kilograms divided by the square of the height in meters.
¶ Obesity is defined as a body-mass index of 30 or higher.
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REGEN-COV Antibody Combination for Covid-19
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 concur-
rently (3.2%) (relative risk reduction, 70.4%; 95%
CI, 31.6 to 87.1; P = 0.002) (Table 2, Figs. 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 (Figs. 2A and
2B). After these f irst 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 randomiza-
tion 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 hospitaliza-
tion 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 Fig. 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
Table 2. Hierarchical End Points.
Hypothesis-Testing Hierarchy and Comparison* Treatment Effect
Relative Risk Reduction
% (95% CI) P Value
Patients with ≥1 Covid-19–related hospitalization or death from
any cause through day 29 — no./total no. (%)
2400 mg vs. placebo 18/1355 (1.3) vs. 62/1341 (4.6) 71.3 (51.7–82.9) <0.001
1200 mg vs. placebo 7/736 (1.0) vs. 24/748 (3.2) 70.4 (31.6–87.1) 0.002
In patients with baseline viral load >10
6
copies/ml, 2400 mg
vs. placebo
13/924 (1.4) vs. 55/876 (6.3) 77.6 (59.3–87.7) <0.001
In patients who were serum antibody–negative at baseline,
2400 mg vs. placebo
12/940 (1.3) vs. 49/930 (5.3) 75.8 (54.7–87.0) <0.001
In patients with baseline viral load >10
6
copies/ml, 1200 mg
vs. placebo
6/482 (1.2) vs. 20/471 (4.2) 70.7 (27.6–88.1) 0.005
In patients who were serum antibody–negative at baseline,
1200 mg vs. placebo
3/500 (0.6) vs. 18/519 (3.5) 82.7 (41.6–94.9) 0.001
Patients with ≥1 Covid-19–related hospitalization or death from
any cause, day 4 through day 29 — no./total no. (%)
2400 mg vs. placebo 5/1351 (0.4) vs. 46/1340 (3.4) 89.2 (73.0–95.7) <0.001
1200 mg vs. placebo 5/735 (0.7) vs. 18/748 (2.4) 71.7 (24.3–89.4) 0.010
Median time to resolution of Covid-19 symptoms — days
2400 mg vs. placebo 10 vs. 14;
4-day faster resolution
<0.001
1200 mg vs. placebo 10 vs. 14;
4-day faster resolution
<0.001
* All analyses were conducted in the modified full analysis set, which included all patients who were confirmed by means of quantified reverse-
transcriptase–polymerase-chain-reaction testing of nasopharyngeal swabs to be positive for severe acute respiratory syndrome coronavirus
2 at randomization and who had at least one risk factor for severe Covid-19. The placebo group of 1341 patients who underwent randomiza-
tion concurrently with the group that received 2400 mg of REGEN-COV included the placebo group of 748 patients who underwent random-
ization concurrently with the group that received 1200 mg of REGEN-COV.
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Patients with Event (%)
100
6
5
4
3
1
2
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29
Trial Day
BCovid-19–Related Hospitalization or Death from Any Cause — Combined Phase 3 Trial
ACovid-19–Related Hospitalization or Death from Any Cause — Amended Phase 3 Trial
Placebo
REGEN-COV, 1200 mg
748
736
744
733
738
728
730
726
727
723
724
723
718
723
716
723
716
721
716
721
715
721
702
708
701
708
690
703
598
624
REGEN-COV, 1200 mg
REGEN-COV, 2400 mg
No. at Risk
Patients with Event (%)
100
6
5
4
3
1
2
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29
Trial Day
CTime to Resolution of Symptoms — Amended Phase 3 Trial
Placebo
REGEN-COV, 2400 mg
1341
1355
1330
1339
1315
1335
1298
1332
1287
1329
1275
1329
1265
1327
1260
1324
1259
1324
1258
1324
1257
1323
1242
1316
1241
1314
1211
1292
1052
1113
No. at Risk
Patients with Resolution of Symptoms
(%)
100
90
80
70
60
50
40
30
20
10
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
Days since Start of Trial Day 1 (baseline)
Placebo
REGEN-COV, 1200 mg
REGEN-COV, 2400 mg
680
673
677
533
534
542
513
514
518
496
485
495
471
452
462
450
423
427
435
393
388
419
367
356
396
332
322
345
278
271
363
307
300
322
259
238
300
239
226
277
219
210
258
208
204
246
193
194
227
182
183
215
170
173
206
154
161
196
138
151
189
132
145
178
130
133
173
124
128
162
118
123
157
114
120
150
110
113
138
110
109
123
100
95
86
58
56
No. at Risk
Placebo
REGEN-COV, 1200 mg
REGEN-COV, 2400 mg
14 (13–16)
10 (9–12)
10 (9–10)
Median Time to Resolution
days (lower limit–upper limit)
Placebo
Placebo
REGEN-COV, 1200 mg REGEN-COV, 2400 mgPlacebo
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REGEN-COV Antibody Combination for Covid-19
with similar improvements in resolution of symp-
toms across subgroups (Fig. S5).
Other Secondary End Points and Additional
Analyses
The incidence of Covid-19–related hospitaliza-
tion 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 telemedi-
cine visit) or death from any cause (Table S9).
The clinical eff icacy 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 hospi-
talizations or deaths overall (Table S14). In pa-
tients 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 place-
bo. 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 log
10
copies per milli-
liter (95% CI, −0.90 to −0.53), −0.86 log
10
copies
per milliliter (95% CI, −1.00 to −0.72), and −0.87
log
10
copies per milliliter (95% CI, −1.07 to −0.67),
respectively (Figs. S6 through S8).
Safet y
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 majorit y were not considered by the investi-
gators to be related to the trial drug. Few pa-
tients 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 safet y events.
Pharmacokinetics
The mean concentrations of casirivimab and
imdevimab in serum increased in a dose-propor-
tional 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 im-
devimab 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 im-
devimab 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
Figure 2 (facing page). Clinical Eff icacy.
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 percent-
age 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.
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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.
Disc ussion
Previous data from the phase 1–2 portion of this
trial showed that in outpatients with Covid-19,
REGEN-COV lowered the viral load, reduced the
need for medical attention related to Covid-19,
and may have reduced the risk of hospitaliza-
tion.
15,16
The phase 3 clinical outcomes data pre-
sented here are consistent with and strengthen
these findings showing that early use of REGEN-
COV in outpatients with risk factors for severe
Covid-19 can lower the risk of hospitalization or
death from any cause. Both doses of intravenous
REGEN-COV (1200 mg and 2400 mg) led to a
reduction in Covid-19–related hospitalization
or death from any cause over a period of 28
days after treatment. The small number of deaths
limited the abilit y to assess the effects of
REGEN-COV on mortality. In patients who were
hospitalized, REGEN-COV led to a shorter dura-
tion of hospitalization and a lower incidence
of ICU-level care. In addition, at both doses,
REGEN-COV resulted in more rapid resolution of
Covid-19 symptoms by a median of 4 days than
placebo. Therefore, a single dose of REGEN-COV
in outpatients with Covid-19 has the potential to
improve patient outcomes and reduce the health
Table 3. Serious Adverse Events and Adverse Events of Special Interest in the Safety Population.*
Event REGEN-COV
Placebo
(N = 1843)
Total
(N = 5531)
1200 mg
(N = 827)
2400 mg
(N = 1849)
8000 mg
(N = 1012)
number of patients (percent)
Serious adverse event that occurred or worsened
during the observation period
Any serious adverse event 9 (1.1) 24 (1.3) 17 (1.7) 74 (4.0) 124 (2.2)
Any serious adverse event of special interest† 1 (0.1) 1 (<0.1) 1 (0.1) 6 (0.3) 9 (0.2)
Adverse events of special interest that occurred or
worsened during the observation period
Grade ≥2 infusion-related reaction within 4
days
2 (0.2) 1 (<0.1) 3 (0.3) 06 (0.1)
Grade ≥2 hypersensitivity reaction within 29
days
01 (<0.1) 01 (<0.1) 2 (<0.1)
Events leading to medical attention at a health
care facility
Related to Covid-19 15 (1.8) 20 (1.1) 11 (1.1) 47 (2.6) 93 (1.7)
Not related to Covid-19 07 (0.4) 05 (0.3) 12 (0.2)
Adverse events that occurred or worsened during
the observation period
Any event 59 (7.1) 142 (7.7) 85 (8.4) 189 (10.3) 475 (8.6)
Grade 3 or grade 4 event 11 (1.3) 18 (1.0) 15 (1.5) 62 (3.4) 106 (1.9)
Event leading to death 1 (0.1) 1 (<0.1) 05 (0.3) 7 (0.1)
Event leading to withdrawal from the trial 01 (<0.1) 2 (0.2) 1 (<0.1) 4 (<0.1)
Event leading to infusion interruption† 1 (0.1) 01 (0.1) 02 (<0.1)
* Events listed here were not present at baseline or were an exacerbation of a preexisting condition that occurred during the observation period,
which is defined as the time from administration of REGEN-COV or placebo to the final follow-up visit.
† Events were defined as hypersensitivity reactions (grade ≥2), infusion-related reactions (grade ≥2), or medical attention at a health care fa-
cility, regardless of whether they were related to Covid-19.
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REGEN-COV Antibody Combination for Covid-19
care burden during this pandemic by reducing
morbidity, including hospitalizations and ICU-
level care. Furthermore, REGEN-COV can speed
up recovery from Covid-19, which is an addi-
tional benefit for patients because there is a
growing body of evidence that some patients,
including those with mild symptoms, will have
a variably prolonged course of recovery.
19 -21
We previously hypothesized that although host
factors play a role in the disease course, the risk
of illness and death associated with SARS-CoV-2
infection may be influenced by a higher viral
burden, such that early use of an anti-spike
monoclonal antibody combination could reduce
this risk.
16
In support of this hypothesis, we
found that patients in the placebo group who
had a Covid-19–related hospitalization or died
had higher baseline viral loads and cleared virus
more slowly than those in the placebo group
who were not hospitalized or did not die. Since
we have found that a higher baseline viral load
is associated with baseline SARS-CoV-2–sero-
negative status, the effect of baseline serologic
status in patients who received placebo was
similarly evaluated in this portion of the trial. In
the initial analysis involving the f irst 275 pa-
tients in the phase 1–2 portion of this trial, we
found that among patients who received placebo,
those who were serum antibody–negative at base-
line had a higher incidence of Covid-19–related
medically attended visits than those who were
serum antibody–positive at baseline. In contrast,
in this larger phase 3 data set, patients in the
placebo group who were serum antibody–posi-
tive at baseline had a similar incidence of hospi-
talization or death as those who were serum
antibody–negative. This suggests that some se-
rum antibody–positive patients have an ineffec-
tive immune response, consistent with the find-
ing that among the patients who received placebo
in this trial, those who were serum antibody–
positive and had a Covid-19–related hospitaliza-
tion or who died had high baseline viral load
levels similar to the levels in those who were
serum antibody–negative and had these events.
Moreover, this trial showed that REGEN-COV is
associated with clinical benefit, regardless of
baseline serum antibody status, so that sero-
logic testing at the time of the Covid-19 diagno-
sis is less critical for making clinical treatment
decisions.
Both the 1200-mg and 2400-mg doses of
REGEN-COV had similar antiviral and clinical
eff icacy. This finding suggests that, in this trial,
REGEN-COV concentrations were above the min-
imally effective dose. Both doses reduced viral
loads, particularly in patients with higher viral
loads, with a faster time to viral clearance than
placebo.
Low incidences of serious adverse events,
hypersensitivity reactions, and infusion-related
reactions were obser ved. Similar to results re-
ported previously,
16
the concentrations of each
antibody in serum from the end of infusion
through day 29 were well above the predicted
neutralization t arget concentration based on in
vitro and preclinical data.
The emergence of resistant variants of SARS-
CoV-2 during treatment with an antiviral agent
or agents or by circulation within the global
community will continue to be a challenge in
the development of effective Covid-19 therapeu-
tic agents and vaccines. In vitro studies and in
vivo animal studies have shown that combina-
tions of noncompeting antibody-based therapeu-
tics, such as REGEN-COV, are able to suppress
the emergence of resistant variants.
12-1 4
REGEN-
COV was also found to protect against the selec-
tion of SARS-CoV-2 variants in an analysis of
spike protein genetic diversity involving 1000
patients with Covid-19 (either outpatients from
this trial or hospitalized patients from a separate
trial [ClinicalTrials.gov number, NCT04426695]).
14
Moreover, the REGEN-COV combination antibody
therapy has had eff icacy in vitro against cur-
rently circulating variants of concern and vari-
ants of interest, including B.1.1.7 (alpha), B.1.351
(beta), B.1.617.2 (delta), and P.1 (gamma).
9,14
The 2400-mg dose of REGEN-COV received
an emergency use authorization (EUA) from the
Food and Drug Administration in November 2020
for the treatment of high-risk outpatients with
mild-to-moderate Covid-19.
22
In June 2021, after
this trial showed that the 1200-mg dose pro-
vided a similar decrease in the risk of hospital-
ization or death and a virologic eff icacy that was
similar to that provided by the 2400-mg dose,
the 1200-mg dose received an EUA (replacing the
2400-mg dose).
22
REGEN-COV has also been in-
cluded in the National Institutes of Health treat-
ment guidelines for high-risk outpatients with
Covid-1 9.
23
The data from this phase 3 trial in-
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volving outpatients with Covid-19 showed that the
1200-mg dose of REGEN-COV, like the 2400-mg
dose, reduced the risk of Covid-19–related hospi-
talization or death and sped the time to recovery.
Supported by Regeneron Pharmaceuticals, F. Hoff mann–La
Roche, and t he Biomedical Advanced Research a nd Develop-
ment Authority of t he Department of Health and Human Ser-
vices, Of fice of the Assista nt Secret ar y for Preparedness and
Response (cont ract number HHSO100201700020C).
Disclosure forms provided by t he author s are ava ilable w ith
the fu ll text of this art icle at NEJM.org.
A data sharing statement provided by the authors is available
with t he full text of this a rticle at NEJM.org.
We thank t he trial participants; t heir fa milies; the investiga-
tiona l site members involved in this trial (principal and subprin-
cipal investigators, listed in t he Supplement ary Appendix); the
Regeneron t ria l team (members listed in t he Supplementary Ap-
pendix); the members of the independent dat a and safety moni-
toring committee; Brian Head, Ph.D., Car yn Trbovic, Ph.D., and
S. Balachandra Dass, Ph.D., of Regeneron Pharm aceuticals for
assistance with development of an ea rlier ver sion of the manu-
script; a nd Prime for assist ance with the format ting a nd copy
editing of an ea rlier version of the manuscript.
Appendix
The authors’ full names and academic degrees are as follows: David M. Weinreich, M.D., Sumathi Sivapalasingam, M.D., Thomas
Norton, M.D., Shazia Ali, Pharm.D., Haitao Gao, Ph.D., Rafia Bhore, Ph.D., Jing Xiao, Ph.D., Andrea T. Hooper, Ph.D., Jennifer D.
Hamilton, Ph.D., Bret J. Musser, Ph.D., Diana Rofail, Ph.D., Mohamed Hussein, Ph.D., Joseph Im, B.S., Dominique Y. Atmodjo, B.A.,
Christina Perry, M.B.A., Cynthia Pan, B.Pharm., Adnan Mahmood, M.D., Romana Hosain, M.D., M.P.H., John D. Davis, Ph.D., Kenneth C.
Turner, Ph.D., Alina Baum, Ph.D., Christos A. Kyratsous, Ph.D., Yunji Kim, Pharm.D., Amanda Cook, B.S., Dip.Reg.Aff., Wendy Kamp-
man, M.D., Lilia Roque-Guerrero, M.D., Gerard Acloque, M.D., Hessam Aazami, M.D., Kevin Cannon, M.D., J. Abraham Simón-Campos,
M.D., Joseph A. Bocchini, M.D., Bari Kowal, M.S., A. Thomas DiCioccio, Ph.D., Yuhwen Soo, Ph.D., Gregory P. Geba, M.D., Dr.P.H.,
Neil Stahl, Ph.D., Leah Lipsich, Ph.D., Ned Braunstein, M.D., Gary Herman, M.D., and George D. Yancopoulos, M.D., Ph.D.
The authors’ affiliations are as follows: Regeneron Pharmaceuticals, Tarrytown (D.M.W., T.N., S.A., H.G., R.B., J.X., A.T.H., J.D.H.,
B.J.M., D.R., M.H., J.I., D.Y.A., C. Perry, C. Pan, A.M., R.H., J.D.D., K.C.T., A.B., C.A.K., Y.K., A.C., W.K., B.K., A.T.D., Y. S., G.P.G.,
N.S., L.L., N.B., G.H., G.D.Y.) and Excision BioTherapeutics, New York (S.S.) — both in New York; Bio-Medical Research (L.R.-G.) and
Universal Medical and Research Center (G.A.) — both in Miami; Hope Clinical Research, Canoga Park, CA (H.A.); PMG Research of
Wilmington, Wilmington, NC (K.C.); Köhler and Milstein Research, Hospital General Agustín O’Horan, Mérida, Mexico (J.A.S.-C.); and
the Willis-Knighton Physician Network, Shreveport, LA (J.A.B).
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