key: cord-0721350-ldi9x8k6
authors: Weinreich, D.; Sivapalasingam, S.; Norton, T. D.; Ali, S.; Gao, H.; Bhore, R.; Xiao, J.; Hooper, A. T.; Hamilton, J. D.; Musser, B. J.; Rofail, D.; Hussein, M.; Im, J.; Atmodjo, D. Y.; Perry, C.; Pan, C.; Mahmood, A.; Hosain, R.; Davis, J. D.; Turner, K. C.; Baum, A.; Kyratsous, C. A.; Kim, Y.; Cook, A.; Kampman, W.; Roque-Guerrero, L.; Acloque, G.; Aazami, H.; Cannon, K.; Simon-Campos, J. A.; Bocchini, J. A.; Kowal, B.; DiCioccio, T.; Soo, Y.; Stahl, N.; Lipsich, L.; Braunstein, N.; Herman, G.; Yancopoulos, G. D.; Investigators, Trial
title: REGEN-COV Antibody Cocktail Clinical Outcomes Study in Covid-19 Outpatients
date: 2021-05-21
journal: nan
DOI: 10.1101/2021.05.19.21257469
sha: e8ce8ca7ebb57156709825d04d153ea5af5f6d27
doc_id: 721350
cord_uid: ldi9x8k6

Background: REGEN-COV antibody cocktail (casirivimab with imdevimab) rapidly reduced viral load and decreased medically-attended visits in the phase 1/2 portion of this trial; REGEN-COV, retains activity in vitro against emerging SARS-CoV-2 variants of concern. Methods: The phase 3 portion of this adaptive, randomized, master protocol, included 4,057 Covid-19 outpatients with one or more risk factors for severe disease. Patients were randomized to a single treatment of intravenous placebo, or various doses of REGEN-COV, and followed for 28 days. The prespecified hierarchical analysis first compared REGEN-COV 2400mg dose vs concurrent placebo, then compared the 1200mg dose vs concurrent placebo, for endpoints assessing risk of hospitalization or death, and time to symptom resolution. Safety was evaluated in all treated patients. Results: Both REGEN-COV 2400mg and 1200mg significantly reduced Covid-19-related hospitalization or all-cause death compared to placebo (71.3% reduction [1.3% vs 4.6%; p<0.0001] and 70.4% reduction [1.0% vs 3.2%; p=0.0024], respectively). The median time to resolution of Covid-19 symptoms was 4 days shorter in both dose arms vs placebo (10 vs 14 days; p<0.0001). Efficacy of REGEN-COV was consistent across subgroups, including patients who were SARS-CoV-2 serum antibody-positive at baseline. REGEN-COV more rapidly reduced viral load than placebo. Serious adverse events occurred more frequently in the placebo group (4.0%) than in the 1200mg (1.1%) and 2400mg (1.3%) groups and grade [≥]2 infusion-related reactions were infrequent (<0.3% in all groups). Conclusions: Treatment with REGEN-COV was well-tolerated and significantly reduced Covid-19-related hospitalization or all-cause death, rapidly resolved symptoms, and reduced viral load. (Funded by Regeneron Pharmaceuticals and the Biomedical and Advanced Research and Development Authority of the Department of Health and Human Services; ClinicalTrials.gov number, NCT04425629.)

SARS-CoV-2 causes coronavirus disease 2019 and, as of April 2021, has infected >130 million people and led to ~3 million deaths globally. 1 Although most Covid-19 patients are managed in the outpatient setting, some will progress to severe illness leading to hospitalization or death. 2-6 Several investigational products, including REGEN-COV™, are available under Emergency Use Authorization but there have been limited clinical data to support their wider use and there are no approved treatments for reducing the risk of hospitalization or death due to Covid-19. There is also a need for therapeutics that remain effective against emerging SARS-CoV-2 variants of concern (VOCs), which contain mutations that attenuate immunity from prior SARS-CoV-2 infection, vaccination, and some monoclonal antibodies. [7] [8] [9] [10] To develop a therapeutic that would retain activity against emerging variants, a highthroughput screen was undertaken to generate an antibody cocktail consisting of two SARS-CoV-2 neutralizing antibodies against distinct, non-overlapping epitopes on the spike protein, resulting in REGEN-COV. [11] [12] [13] In vitro studies demonstrated that REGEN-COV retains activity against current VOCs and variants of interest (VOIs), including B.1.1.7, B.1.429, and E484K-containing variants, such as B.1.351, P.1, and B.1.526. 9, 14 In the phase 1/2 portion of this adaptive phase 1-3 randomized, placebo-controlled master protocol, REGEN-COV demonstrated efficacy in symptomatic outpatients, where it rapidly reduced viral load and the need for medical attention related to 16 On February 19 th , 2021, an independent data monitoring committee (IDMC) recommended stopping enrollment of patients into the placebo group of the phase 3 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

This was an adaptive, multicenter, randomized, double-blind, placebo-controlled, phase 1/2/3 master protocol in Covid-19 outpatients (NCT04425629). The phase 3 portion comprised 3 cohorts: Cohort 1 (≥18 years), Cohort 2 (<18 years), and Cohort 3 (pregnant at randomization). Initially, phase 3 patients were randomized 1:1:1 to receive intravenous (IV) placebo, REGEN-COV 2400mg (1200mg each of casirivimab and imdevimab), or REGEN-COV 8000mg (4000mg each antibody) ( Figure S1 ). Based upon phase 1/2 results that showed the 2400mg and 8000mg 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 th , 2020 so that subsequent patients enrolled had ≥1 risk factor for severe Covid-19 and were randomized 1:1:1 to receive placebo, REGEN-COV 1200mg (600mg each antibody) IV, or REGEN-COV 2400mg (1200mg each antibody) IV. On February 19 th , 2021, per IDMC recommendation, patients were no longer randomized to receive placebo. The phase 3 primary efficacy analysis presented here is comprised of Cohort 1 patients randomized to REGEN-COV 2400mg or 1200mg, with their concurrent placebo groups serving as a control.

Regeneron designed the trial; gathered the data, together with the trial investigators;

and analyzed the data. Regeneron and the authors vouch for the accuracy and completeness of the data, and Regeneron vouches for the fidelity of the trial to the . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The investigators, site personnel, and Regeneron employees who were involved in collecting and analyzing data were unaware of the treatment-group assignments. An independent data monitoring committee monitored unblinded data to make recommendations about trial modification 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 applicable regulatory requirements. The local institutional review board or ethics committee at each study center oversaw trial conduct and documentation. All patients provided written informed consent before participating in the trial.

Eligible patients (Cohort 1) were ≥18 years of age and non-hospitalized, with a confirmed local SARS-CoV-2-positive diagnostic test result ≤72 hours and onset of any Covid-19 symptom, as determined by the investigator, ≤7 days before randomization.

Randomization into the initial phase 3 portion was stratified by country and presence of risk factors for severe Covid-19. In the amended phase 3 portion, only patients with ≥1 risk factor for severe Covid-19 were eligible. The full list of inclusion and exclusion criteria can be found in the Protocol.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 21, 2021. ; https://doi.org/10.1101/2021.05.19.21257469 doi: medRxiv preprint All patients were assessed at baseline for anti-SARS-CoV-2 antibodies -anti-spike [S1]

IgA, anti-spike [S1] IgG, and anti-nucleocapsid IgG -and grouped for analyses as serum antibody-negative (if all available test results were negative), serum antibodypositive (if any available test result was positive), or other (inconclusive/unknown results).

At baseline (day 1), REGEN-COV (diluted in normal saline solution) or saline placebo was administered intravenously. Hospitalizations were assessed to be related to Covid-19 by the investigator. The Symptoms Evolution of COVID-19 (SE-C19) instrument, an electronic diary, recorded 23 Covid-19 symptoms daily. 17 Quantitative virologic analysis of nasopharyngeal (NP) swab samples and serum antibody testing were conducted in a central laboratory and were previously described. 16 Additional details on assessments are described in the Supplementary Appendix.

The primary and two key secondary endpoints were tested hierarchically (Table S1 ).

The primary endpoint was the proportion of patients with ≥1 Covid-19-related hospitalization or all-cause death through day 29. The key secondary clinical endpoints were (1) the proportion of patients with ≥1 Covid-19-related hospitalization or all-cause death from day 4 through day 29 and (2) the time to Covid-19 symptoms resolution (19 of the 23 recorded symptoms). Time to Covid-19 symptoms resolution was defined as time from randomization to the first day during which the patient scored "no symptom' . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 21, 2021. ; https://doi.org/10.1101/2021.05.19.21257469 doi: medRxiv preprint (score=0) on all 19 symptoms except cough, fatigue, and headache, which could have been scored as "mild/moderate symptom" (score=1) or "no symptom" (score=0).

Safety endpoints for the phase 3 portion of the trial included serious adverse events (SAEs) that occurred or worsened during the observation period and adverse events of special interest (AESIs): grade ≥2 hypersensitivity reactions, grade ≥2 infusion-related reactions, and treatment-emergent adverse events (TEAEs) requiring medical attention at a healthcare facility.

The statistical analysis plan for the presented analysis was finalized prior to database lock and unblinding of phase 3 Cohort 1; the primary analysis did not include patients from the previously reported phase 1/2 portion of the trial. 16 The full analysis set (FAS) included all randomized symptomatic patients. Efficacy analyses were performed based on a modified FAS (mFAS) defined as all randomized patients with a positive SARS-CoV-2 central lab-determined RT-qPCR test at baseline and with ≥1 risk factor for severe Covid-19. Safety was assessed in treated patients in the FAS.

The proportion of patients with ≥1 Covid-19-related hospitalization or all-cause death was compared between each dose group and concurrent placebo using the stratified Cochran-Mantel-Haenszel (CMH) test with country as a stratification factor. P-values from the stratified CMH test and 95% confidence intervals (CIs) for the relative risk reduction using the Farrington-Manning method are presented. Time to . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 21, 2021. ; https://doi.org/10.1101/2021.05.19.21257469 doi: medRxiv preprint symptoms resolution was assessed in patients with a baseline total severity score >3 and analyzed using the stratified log-rank test with country as a stratification factor.

Median times and associated 95% CIs were derived from the Kaplan-Meier method.

The hazard ratio and 95% CI were estimated by the Cox regression model.

Analyses of the primary and key secondary endpoints were conducted at a two-sided α=0.05 utilizing a hierarchical testing strategy to control for type I error (Table S1 ).

Statistical analyses were performed with SAS software, v9.4 (SAS Institute). Additional statistical methods are described in the Supplementary Appendix.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 21, 2021. ; https://doi.org/10.1101/2021.05.19.21257469 doi: medRxiv preprint

Phase 3 patients were enrolled between September 24 th , 2020 and January 17 th , 2021.

Initially, in the original phase 3 portion, a total of 3088 patients, with or without risk factors for severe Covid-19, were randomized to receive a single dose of either placebo, REGEN-COV 8000mg or REGEN-COV 2400mg. In the amended phase 3 portion, an additional 2519 patients with ≥1 risk factor were randomized to receive a single dose of placebo, REGEN-COV 2400mg or REGEN-COV 1200mg ( Figure 1 ). Patients had a median follow-up of 45 days, with 96.6% of patients having >28 days follow-up.

The primary efficacy population included those with ≥1 risk factor for severe Covid-19 and a baseline central laboratory test positive for SARS-CoV-2 (mFAS) (Figure 1 ).

Among the mFAS population (n=4057), demographic and baseline medical characteristics were balanced between the placebo and REGEN-COV groups (Table 1) .

For the overall mFAS population, median age was 50 years (interquartile range [IQR] 38-59), 49% were male, 14% ≥65 years, and 35% were Hispanic; the most common risk factors were obesity (58%), age ≥50 years (52%), and cardiovascular disease (36%); 3% of patients were immunosuppressed or on immunosuppressive medications (Table   S2 ).

The median NP viral load was 6.98 log10 copies/mL (IQR 5.45-7.85) and the majority of patients (69%) were SARS-CoV-2 serum antibody-negative at baseline (Table 1) ; these high viral loads and lack of endogenous immune response at baseline suggested that enrolled individuals were early in the course of their infection. Patients had a median of . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 21, 2021. ; https://doi.org/10.1101/2021.05.19.21257469 doi: medRxiv preprint antibody-negative status, and median days of Covid-19 symptoms at randomization were similar across treatment groups. Demographic and baseline medical characteristics for the REGEN-COV 8000mg mFAS group and concurrent placebo are shown in Table S3 .

When considering placebo-treated patients only, there was an association between baseline viral load and Covid-19-related hospitalization or all-cause death: hospitalization/deaths occurred in a greater proportion of patients with high baseline viral load (>10 6 copies/mL) compared to those with lower viral load (≤10 6 copies/mL) (6.3% [55/876] vs 1.3% [6/457]; Table S4 ).

Patients in the placebo group who were serum antibody-negative at baseline had higher median viral loads at baseline compared to those who were serum antibody-positive (7.45 log10 copies/ml vs 4.96 log10 copies/ml), and took longer to bring their viral levels to below the lower limit of quantification ( Figure S2 ).

Despite these population-level observations, baseline serum antibody status of placebotreated patients was not predictive of subsequent Covid-19-related hospitalizations or all-cause death, as these rates were similar in patients who were serum antibodynegative and antibody-positive (5.3% [49/930] vs 4.0% [12/297] ; Table S4 ). The lack of positive-predictive value of serum antibody-positive status on the reduction in rates of hospitalization or death suggests that some patients mount an ineffective immune . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 21, 2021. ; https://doi.org/10.1101/2021.05.19.21257469 doi: medRxiv preprint response. For example, placebo patients who were serum antibody-positive but still progressed to requiring hospitalization or died had high viral loads at baseline and day 7, similar to patients who were serum antibody-negative and required hospitalization or died (Table S5) . Figure S3 ).

The reduction in the proportion of patients with Covid-19-related hospitalization or allcause death was observed starting approximately 1-3 days after treatment with REGEN-COV (Figure 2A-B Figure S4 ).

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The median time to resolution of Covid-19 symptoms was 4 days earlier in both REGEN-COV dose groups than in the placebo groups (10 days vs 14 days, respectively; p<0.0001 each for 2400mg and 1200mg) (Table 2; 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 symptoms resolution across subgroups ( Figure S5 ).

All REGEN-COV dose levels (1200mg, 2400mg, and 8000mg) led to similar and rapid declines in viral load compared to placebo ( Figure S6-S8) .

REGEN-COV treatment was associated with a lower proportion of patients with Covid-19-related hospitalization (Table S7 ). Among patients that were hospitalized due to Covid-19, those in the REGEN-COV group had shorter hospital stays and a lower rate of admission to an intensive care unit (Table S8) .

REGEN-COV treatment was associated with a lower proportion of patients with Covid-19-related hospitalization, emergency room visits, or all-cause death through Day 29 (Table S9 ) and a lower proportion requiring any medically-attended visit for worsening Covid-19 (hospitalization, emergency room visit, urgent care visit or physician office/telemedicine visit) or all-cause death (Table S7; Table S10 -S11).

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) (Table 3) . More patients experienced TEAEs that resulted in death in the placebo group (5 patients, 0.3%) compared to the REGEN-COV dose groups: 1 (0.1%) in 1200mg, 1 (<0.1%) in 2400mg, and 0 in 8000mg (Table   3 ; Table S12 ). Most adverse events were consistent with complications of Covid-19 (Table S13 ) and the majority were not considered to be related to study drug. Few patients experienced grade ≥2 infusion-related reactions (0 in placebo; 2, 1, and 3 patients in 1200mg, 2400mg, and 8000mg, respectively) and hypersensitivity reactions (1 in placebo and 1 in 2400mg) ( Table 3) . A similar safety profile was observed between REGEN-COV doses, with no discernable imbalance in safety events.

The mean concentrations of casirivimab and imdevimab in serum on day 29 increased in a dose-proportional manner and were consistent with linear pharmacokinetics (Table   S14 ). The mean day 29 concentrations of casirivimab and imdevimab in serum were 46.4±SD22.5 and 38.3±SD19.6 mg/L, respectively, for the 1200mg dose and 73.2±SD27.2 and 60.0±SD22.9 mg/L, respectively, for the 2400mg dose; the mean estimated half-life was 28.8 days for casirivimab and 25.5 days for imdevimab (Table   S14 ).

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Covid-19 has the potential to improve patient outcomes and substantially reduce the health care burden experienced during this pandemic by reducing morbidity and mortality, including hospitalizations and ICU-level care. Furthermore, REGEN-COV can substantially speed up recovery from Covid-19, which represents an additional benefit for patients as there is a growing body of evidence that some patients, including those with mild symptoms, will have a variably prolonged course of recovery. [18] [19] [20] We previously hypothesized that, while host factors play a role in the disease course, the morbidity and mortality of SARS-CoV-2 result from high viral burden such that early treatment with an anti-spike monoclonal antibody combination could reduce this risk. In the placebo group, we found that patients with hospitalizations or all-cause death had markedly higher viral loads at baseline and were slower to clear virus, independent of . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 21, 2021. ; https://doi.org/10.1101/2021.05.19.21257469 doi: medRxiv preprint

A data sharing statement provided by the authors is available with the full text of this article. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 21, 2021. ; https://doi.org/10.1101/2021.05.19.21257469 doi: medRxiv preprint manuscript; and Prime for formatting and copy editing suggestions for an earlier version of the manuscript.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 21, 2021. ; Table 1 Patients with event that led to infusion interruption* 0 1 (0.1) 0 1 (<0.1) 2 (<0.1) * Events were hypersensitivity reactions (grade ≥2), infusion-related reactions (grade ≥2), or medical attention at a healthcare facility, regardless of relation to Covid-19. † 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. 

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Coronavirus Disease 2019 Case Surveillance -United States

Factors associated with COVID-19-related death using OpenSAFELY

Characteristics of and Important Lessons From the

COVID-19) Outbreak in China: Summary of a Report of

Cases From the Chinese Center for Disease Control and Prevention

Risk of mortality in patients infected with SARS-CoV-2 variant of concern 202012/1: matched cohort study

Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England

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Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail

Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies

REGN-COV2 antibodies prevent and treat SARS-CoV-2 infection in rhesus macaques and hamsters

In vitro and in vivo preclinical studies predict REGEN-COV protection against emergence of viral escape in humans. bioRxiv 2021. 15. FDA. Fact Sheet for Health Care Providers -Emergency Use Authorization

REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19

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Post-acute COVID-19 syndrome

Letter of Authorization for Emergency Use of REGEN-COV (casirivimab * In the original phase 3 portion of the trial, Regeneron requested that 2, 1, and 5 patients in the placebo, 2400 mg, and 8000 mg groups, respectively, withdraw from the trial as these patients did not meet the inclusion/exclusion criteria (ie, were randomized in error)

Regeneron requested that 2, 4, and 2 patients in the placebo, 1200 mg, and 2400 mg groups, respectively, withdraw from the trial as these patients did not meet the inclusion/exclusion criteria (ie

mFAS, modified full analysis set

RT-qPCR, reverse transcriptase quantitative polymerase chain reaction

REGEN-COV 1200 mg, REGEN-COV 2400 mg