key: cord-0852624-wx6md0k5
authors: Somersan-Karakaya, S.; Mylonakis, E.; Menon, V. P.; Wells, J. C.; Ali, S.; Sivapalasingam, S.; Sun, Y.; Bhore, R.; Mei, J.; Miller, J.; Cupelli, L.; Hooper, A. T.; Hamilton, J. D.; Pan, C.; Pham, V.; Zhao, Y.; Hosain, R.; Mahmood, A.; Davis, J. D.; Turner, K. C.; Kim, Y.; Cook, A.; Kowal, B.; Soo, Y.; DiCioccio, A. T.; Geba, G. P.; Stahl, N.; Lipsich, L.; Braunstein, N.; Herman, G. A.; Yancopoulos, G. D.; Weinreich, D. M.; Team, the Covid-19 Phase 23 Hospitalized Trial
title: REGEN-COV for the Treatment of Hospitalized Patients with Covid-19
date: 2021-11-08
journal: nan
DOI: 10.1101/2021.11.05.21265656
sha: 3fa5ea9786532cccf105b44568fff826438ba0ff
doc_id: 852624
cord_uid: wx6md0k5

Background: Hospitalized patients with Covid-19 experience high mortality rates, ranging from 10-30%. Casirivimab and imdevimab (REGEN-COV) is authorized in various jurisdictions 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 REGEN-COV, but in most of the world, anti-spike monoclonal antibody therapy is currently not approved for use in hospitalized patients. Methods: In this phase 1/2/3 double-blind placebo-controlled trial, patients on low-flow or no supplemental oxygen hospitalized with Covid-19 were randomized (1:1:1) to 2.4 g or 8.0 g REGEN-COV or placebo and characterized at baseline for viral load and SARS-CoV-2 endogenous immune response. Results: 1336 patients on low-flow or no supplemental oxygen were treated. The primary endpoint was met: in seronegative patients, the LS mean difference (REGEN-COV vs. placebo) for TWA change from baseline viral load was -0.28 log10 copies/mL (95% CI: -0.51, -0.05; P=0.0172). The primary clinical analysis of death or mechanical ventilation from day 6-29 in patients with high-viral load had a strong positive trend but did not reach significance. REGEN-COV reduced all-cause mortality in seronegative patients through day 29 (RRR, 55.6%; 95% CI: 24.2%, 74%). No safety concerns were noted overall nor in seropositive patients. Conclusions: In hospitalized patients with Covid-19 on low-flow or no oxygen, REGEN-COV 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. (ClinicalTrials.gov number, NCT04426695.)

The clinical progression of coronavirus disease 2019 , caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is highly variable; while many cases manifest with relatively mild symptoms, others progress to severe respiratory failure requiring supplemental oxygen and/or mechanical ventilation. [1] [2] [3] [4] Casirivimab and imdevimab (REGEN-COV ® ) is a monoclonal antibody combination approved or authorized for emergency use for the treatment of outpatients with mild to moderate Covid-19 and for post-exposure prophylaxis in the United States and other jurisdictions. [5] [6] [7] In outpatients with Covid-19, REGEN-COV reduced hospitalization or all-cause death, reduced viral load, and shortened symptom duration. 8-10 Data show REGEN-COV is also highly effective in preventing asymptomatic as well as symptomatic Covid-19, evidenced by a single-dose subcutaneous administration in showing ~80% lower risk of developing Covid-19 for household contacts living with an infected individual. 11 The totality of evidence suggests that benefit is greatest when treated early. 12 Based on the potent anti-viral activity of REGEN-COV it was prospectively hypothesized that reducing viral burden as early as possible would also decrease morbidity and mortality associated with SARS-CoV-2 infection in hospitalized patients. In a recent open label platform trial of hospitalized patients with Covid-19 in the United Kingdom (RECOVERY), REGEN-COV met its primary endpoint in improving overall survival in patients who had not mounted their own immune response at baseline (seronegative) by 20%, and also improved duration of hospitalization. 13 Here, we describe the final efficacy and safety results from the first . 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 November 8, 2021. ; https://doi.org/10.1101/2021.11.05.21265656 doi: medRxiv preprint 5 phase 1/2/3 double-blind placebo-controlled trial of REGEN-COV in hospitalized patients with Covid-19 on low-flow or no supplemental oxygen.

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The copyright holder for this preprint this version posted November 8, 2021. ; https://doi.org/10.1101/2021.11.05.21265656 doi: medRxiv preprint 1A) and phase 3 for patients requiring low-flow oxygen (cohort 1); together, these patients are the subject of this manuscript. As phase 1/2 data from patients on lowflow oxygen was previously unblinded in an interim analysis on December 22, 2020, it was not included in the phase 3 efficacy analyses. For patients requiring highintensity oxygen (cohort 2) or mechanical ventilation (cohort 3), enrollment was paused and data were not included due to low sample size; this is further described in the Trial Adaptations section in the Supplementary Appendix.

The primary virologic efficacy endpoint was the time-weighted average (TWA) daily change from baseline (day 1) viral load in nasopharyngeal samples through day 7. 10 The primary clinical efficacy endpoint was the proportion of patients who died or required mechanical ventilation from day 6-29 and day 1-29. Secondary efficacy endpoints examined all-cause mortality and discharge from/readmission to hospital.

Safety endpoints included the proportion of patients with treatment-emergent serious adverse events (SAEs) and adverse events of special interest (AESIs): infusionrelated reactions (IRRs) through day 4, and grade ≥ 2 hypersensitivity reactions through day 29.

The statistical analysis plan was finalized prior to database lock and unblinding. The full analysis set (FAS) was used for safety analyses and includes all randomized patients who received any amount of study drug. The modified FAS (mFAS) was used for efficacy analyses and excludes patients who had negative central lab SARS-CoV-2 RT-qPCR at baseline. . 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 November 8, 2021. ; https://doi.org/10.1101/2021.11.05.21265656 doi: medRxiv preprint Primary endpoint analyses are described in more detail in the Supplementary Appendix. As the trial was stopped earlier than planned (due to low enrollment prior to the surge associated with the Delta variant), the sample size was smaller than anticipated and it was elected to combine the REGEN-COV dose groups and pool patients on no supplemental oxygen (phase 2) and low-flow oxygen (phase 3) for efficacy measures. To control alpha at an 0.05 level, the primary endpoints were tested hierarchically (Table S1 ). After virologic efficacy, the first two clinical endpoints were the proportion of patients who died or went on mechanical ventilation for REGEN-COV vs. placebo from 1) day 6-29 in high-viral load patients and 2) day 6-29 in seronegative patients. High viral load was selected based on previous experience with treatment in the outpatient setting 8,10 ; it was expected that the highviral load population would be highly correlated with the seronegative population, and assessing viral load could be easier than assessing serostatus in a clinical setting.

Safety was assessed in separate analyses for patients receiving no supplemental oxygen (phase 2) and low-flow oxygen (phase 1/2/3). Prespecified subgroup analyses using baseline serostatus and viral load were selected based on previous results. 10 Sample size calculations and missing data handling are described in the Supplementary Appendix.

Details are provided 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. (which was not certified by peer review)

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As of April 9, 2021, 1364 patients on low-flow or no supplemental oxygen were randomized into the study, of whom 1336 were treated. Of those, 1197 (89.6%) tested positive centrally for SARS-CoV-2 (constituting the mFAS) with 406, 398, and 393 in the REGEN-COV 2.4 g, 8.0 g, and placebo groups, respectively (Fig. S2 ).

Baseline demographics were well-balanced. Table S2 .

REGEN-COV significantly reduced viral load in seronegative patients on low-flow or no supplemental oxygen; the least-squares (LS) mean (95% confidence interval [CI]) TWA daily change in viral load from baseline through day 7 was -1.03 log 10 copies/mL (CI: -1.22, -0.84) in the placebo group compared with -1.31 log 10 copies/mL (CI: -1.43, -1.18) in the REGEN-COV combined dose group, with an LS mean difference vs. placebo of -0.28 log 10 copies/mL (CI: -0.51, -0.05; P=0.0172) ( Table 2) .

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The copyright holder for this preprint this version posted November 8, 2021. ; https://doi.org/10.1101/2021.11.05.21265656 doi: medRxiv preprint Both doses of REGEN-COV exhibited similar viral load reductions, showing improvement over placebo starting at day 3 and reaching significance at day 7, after which viral load in the REGEN-COV groups continued to fall relative to placebo ( Fig.   1, Fig S3) . The maximum LS mean differences versus placebo in seronegative patients were at day 7 (described above), day 9 (-0.47 log 10 copies /mL, CI: -0.71, -0.23), and day 11 (-0.59 log 10 copies/mL CI: -0.85, -0.34) (Fig. 1A) . The overall population LS mean fell below the lower limit of quantification (LLOQ; 2.85 log 10 copies/mL) 2 days earlier with REGEN-COV (day 9 REGEN-COV vs. 

Endpoints were examined both from day 1-29 and day 6-29, and were evaluated in the seronegative, high-viral load, and overall populations, as described in the Methods. The analyses presented herein examine the pooled REGEN-COV dose group and pooled cohorts for low-flow and no supplemental oxygen (Fig. 2) .

Individual dose groups of 2.4 g and 8.0 g of REGEN-COV (Fig. S4 ) and separate cohorts by respiratory status (Fig. S5) were also examined and showed trends of benefit across all clinical endpoints.

In the statistical hierarchy (Table S1 ), the first test for clinical efficacy on the endpoint of death or mechanical ventilation in the high-viral load population from day 6-29 showed a numerically lower risk compared to placebo but did not reach statistical significance (relative risk reduction [RRR], 25.5%; 95% CI: -16.2%, 52.2%;

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The copyright holder for this preprint this version posted November 8, 2021. P=0.2) ( Table 2) ; accordingly, all subsequent clinical efficacy analyses are considered descriptive. The second test for clinical efficacy on the endpoint of death or mechanical ventilation in the seronegative population from day 6-29 showed an RRR of 47.1% (CI: 10.2%, 68.8%) ( Table 2 ). Improvements were also observed from day 6-29 in the overall population (RRR, 24.2%; 95% CI: 10.9%, 48.2%) ( Table 2) .

Treatment with REGEN-COV led to a reduction in the proportions of patients who died or required mechanical ventilation, with improvement from day 1-29 in the high-viral load (RRR, 35.0%; 95% CI: 6.6%, 54.8%), seronegative (RRR, 47.0%; 95% CI: 17.7%, 65.8%), and overall (RRR, 30.9%; 95% CI, 5.4% to 49.5%) populations ( Table 2 ). While seronegative patients exhibited the greatest benefit from REGEN-COV treatment, no meaningful benefit or harm was observed in seropositive patients (RRR, 19.5%; 95% CI: -32.8%, 51.2%) ( Fig. 2A ).

Treatment with REGEN-COV led to improvement in all-cause mortality through day 29 in the seronegative, high-viral load, and overall populations. The greatest reduction in the relative risk of death occurred in seronegative patients; 24/360 (6.7%) died within 28 days in the REGEN-COV group, compared to 24/160 (15.0%) in the placebo group (RRR, 55.6%; 95% CI: 24.2%, 74%) (Fig. 2B) . No harm or meaningful benefit was observed in the seropositive population ( Fig. 2A) . For the overall population, driven by the seronegative group, a substantial reduction in death was observed in which 59/804 patients (7.3%) died within 28 days in the REGEN-COV combined dose group, compared to 45/393 patients (11.5%) in the placebo group (RRR, 35.9%; 95% CI: 7.3%, 55.7%) (Fig. 2B) . The improvement in all-cause mortality with REGEN-COV persisted through study day 57 (Fig. S6 ). Similar results . 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 November 8, 2021. ; https://doi.org/10.1101/2021.11.05.21265656 doi: medRxiv preprint were also observed in the secondary endpoints of hospital discharge and readmission, shown in Table S3 and Table S4 Table 3) . AESIs are further detailed in Table S7 and Table S8. . 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 November 8, 2021. ; https://doi.org/10.1101/2021.11.05.21265656 doi: medRxiv preprint DISCUSSION REGEN-COV is a potent antiviral monoclonal antibody combination shown to rapidly reduce SARS-CoV-2 viral load and modulate a patient's disease course across various populations. 8-11,14 REGEN-COV, which contains two distinct neutralizing antibodies, 15,16 retains neutralizing potency against viral variants of concern, including the Beta, Gamma, and Delta variants. 17

Hospitalized patients with Covid-19 experience high mortality rates, ranging from 10-30%. 4 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 November 8, 2021. 27 Recently, interleukin-6 . 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 November 8, 2021. ; https://doi.org/10.1101/2021.11.05.21265656 doi: medRxiv preprint inhibitors such as tocilizumab and sarilumab were recommended by the World Health Organization for use in hospitalized patients, in which they reduced mortality by 13%. 28, 29 The Food and Drug Administration-approved medication remdesivir has shown neither a reduction in viral load nor a mortality benefit in hospitalized patients. 30 REGEN-COV's mechanism of action and safety profile should allow combination approaches with any or all of these other agents.

The safety profile of REGEN-COV in patients on low-flow or no supplemental oxygen was consistent with that observed previously in outpatients and hospitalized patients with Covid-19, 10,13 showing low rates of infusion-related and hypersensitivity reactions, as expected for a fully human antibody against an exogenous target.

Overall, REGEN-COV was well tolerated. The placebo group experienced a greater frequency of SAEs and adverse events leading to death than the REGEN-COV group, consistent with the clinical benefit of treatment.

The respiratory status of the population in this manuscript includes those receiving low-flow or no supplemental oxygen, as the study did not enroll sufficient numbers of patients on high-intensity oxygen or mechanical ventilation prior to pausing of these cohorts due to potential safety imbalances, which were not observed in the much larger RECOVERY trial. 21 The absence of full representation across the spectrum of hospitalized patients on varying degrees of oxygen support is a limitation of this study. Additionally, this study was prematurely terminated due to slow recruitment prior to the current surge associated with the emergence of the Delta variant. As a result of the smaller sample size, key analyses pooled the two patient cohorts as well as the two doses. Sensitivity analyses did not reveal major efficacy differences across the cohorts or doses; minor variability in the magnitude 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. 

Disclosure forms provided by the authors are available with the full text of this article.

Qualified researchers may request access to study documents (including the clinical study report, study protocol with any amendments, blank case report form, and statistical analysis plan) that support the methods and findings reported in this manuscript. Individual anonymized participant data will be considered for sharing once the indication has been approved by a regulatory body, if there is legal authority to share the data and there is not a reasonable likelihood of participant reidentification. Submit requests to https://vivli.org/.

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The copyright holder for this preprint this version posted November 8, 2021. variants of concern: a cohort study. Lancet Infect Dis. 2021/08/31 ed2021. . 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.

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The copyright holder for this preprint this version posted November 8, 2021. ; https://doi.org/10.1101/2021.11.05.21265656 doi: medRxiv preprint Median (Q1:Q3)log 10 copies/ml 6.3 (5.0:7.6) 6.4 (5.1:7.6) 6.5 (5.3:7.8) 6.4 (5.1:7.7)) 6.4 (5. . 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 November 8, 2021. 2019; IV, intravenous; NLR, neutrophil lymphocyte ratio; and SD, standard deviation. †The body-mass index is the weight in kilograms divided by the square of the height in meters. ‡Not requiring high-flow oxygen devices.

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The copyright holder for this preprint this version posted November 8, 2021. ; https://doi.org/10.1101/2021.11.05.21265656 doi: medRxiv preprint therapies and non-antiviral therapies) as fixed effects, and baseline viral load and treatment*baseline as covariates. Negative changes imply improvement in viral load. §95% CI for the relative risk and relative risk reduction (1 -relative risk) uses the Farrington-Manning method. ¶P-value is derived from the Cochran-Mantel-Haenszel test stratified by the type of background standard of care (antiviral therapies and non-antiviral therapies). If np ≤ 5 or n(1-p) ≤ 5 in any treatment group, P-value is based on Fisher's exact test. Nominally significant P-values were omitted.

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The copyright holder for this preprint this version posted November 8, 2021. ; https://doi.org/10.1101/2021.11.05.21265656 doi: medRxiv preprint *AESI denotes adverse event of special interest IV, intravenous; SAE, serious adverse event; and TEAE, treatment-emergent adverse event. †TEAEs collected include treatment-emergent SAEs, AESIs, and grade 3/4 TEAEs, as well as ad-hoc/voluntarily reported TEAEs by some sites.

Phase 1/2/3 cohort 1. §Deemed treatment-related as per investigator assessment.

Phase 2 cohort 1A.

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Panel A graph shows LS mean viral load following administration of REGEN-COV (2.4 g, 8.0 g, or combined analysis of 2.4 and 8.0 g) or placebo for patients who tested negative for all SARS-CoV-2 antibodies at baseline (seronegative). Panel B shows the same but for patents who tested positive for any SARS-CoV-2 antibody at baseline (seropositive). For both panels, the lower limit of quantification is 2.85 log 10 copies/mL. CI denotes confidence-interval; IV, intravenous; mFAS, modified full analysis set; LS, least-squares; PBO, placebo; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SE, standard error; and TWA, timeweighted average.

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