key: cord-0731841-183rv57e
authors: Isa, F.; Forleo-Neto, E.; Meyer, J.; Zheng, W.; Rasmussen, S.; Armas, D.; Oshita, M.; Brinson, C.; Folkerth, S.; Faria, L.; Heirman, I.; Sarkar, N.; Musser, B. J.; Bansal, S.; O'Brien, M. P.; Turner, K. C.; Ganguly, S.; Mahmood, A.; Dupljak, A.; Hooper, A. T.; Hamilton, J. D.; Kim, Y.; Kowal, B.; Soo, Y.; Geba, G. P.; Lipsich, L.; Braunstein, N.; Yancopoulos, G. D.; Weinreich, D.; Herman, G. A.; Team, the COVID-19 Multi-dose Trial
title: Repeat Subcutaneous Administration of REGEN-COV(R) in Adults is Well-Tolerated and Prevents the Occurrence of COVID-19
date: 2021-11-16
journal: nan
DOI: 10.1101/2021.11.10.21265889
sha: 737fc3f8fa73a1e4b5cb03c0792e6b685a3ff77a
doc_id: 731841
cord_uid: 183rv57e

Background: Data show that a single dose of casirivimab and imdevimab (REGEN-COV(R)) is effective in treating hospitalized individuals and outpatients with COVID-19 and in post-exposure prophylaxis. We present results from a phase 1, double-blind, placebo-controlled trial evaluating the safety, tolerability, and efficacy of repeat monthly doses of subcutaneous (SC) REGEN-COV in uninfected adult volunteers who were healthy or had chronic stable medical conditions. Methods: Subjects were randomized (3:1) to SC REGEN-COV 1200 mg or placebo dosed every 4 weeks for up to 6 doses. The primary and secondary endpoints evaluated the safety, pharmacokinetics, and immunogenicity of multiple-dose administration of REGEN-COV. Efficacy was evaluated by the incidence of COVID-19 or SARS-CoV-2 seroconversion. Results: In total, 969 subjects were treated. Repeat monthly dosing of SC REGEN-COV led to a 92.4% relative risk reduction in clinically-defined COVID-19 compared to placebo (3/729 [0.4%] vs 13/240 [5.4%]; odds ratio: 0.07 [95% CI, 0.01-0.27]), and a 100% reduction in laboratory-confirmed COVID-19 (0/729 vs 10/240 [4.2%]; odds ratio 0.00). Development of anti-drug antibodies was low (<5% subjects). No grade [≥]3 injection-site reactions (ISRs) or hypersensitivity reactions were reported. A slightly higher percentage of subjects reported TEAEs with REGEN-COV (54.9%) than placebo (48.3%), due to ISRs (all grade 1-2). Serious adverse events were rare and occurred at similar percentages in the REGEN-COV and placebo groups. No deaths were reported in the 6-month treatment period. Conclusions: Repeated monthly administration of 1200 mg SC REGEN-COV was well-tolerated with low immunogenicity, and showed a substantial risk reduction in COVID-19 occurrence. (ClinicalTrials.gov identifier, NCT04519437)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causal agent of coronavirus disease 2019 (COVID-19), [1] [2] [3] which emerged in December 2019 and was declared a global pandemic in March 2020. [4] [5] [6] Other than vaccines, there are currently no approved therapies that can be used for chronic prevention of COVID-19. 7, 8 Such treatments are urgently needed, especially in populations who are immunocompromised or have a medical condition or other reason making them unlikely to respond to or be protected by vaccination. 9 Casirivimab and imdevimab (REGEN-COV ® ) is a combination of distinct neutralizing monoclonal antibodies that simultaneously bind non-overlapping epitopes of the receptor binding domain of the SARS-CoV-2 spike protein, thereby preventing the virus from infecting host cells. [10] [11] [12] Preclinical and human studies indicate that administering these 2 antibodies in combination provides potent neutralization against currently circulating viral variants of concern including beta, gamma, epsilon, and delta variants, and may protect against the selection of new treatment-resistant SARS-CoV-2 variants. 10,13 Previous trials with REGEN-COV have shown clinical benefit in the treatment setting, reducing the likelihood of hospitalization and death by over 70% in high-risk SARS-CoV-2 infected outpatients, 14, 15 and by reducing mortality in seronegative hospitalized patients by 21%. 16 Additionally, a single dose of REGEN-COV reduced both infection and symptomatic COVID-19 in close contacts of infected individuals. 17 On the basis of these studies, REGEN-COV is currently authorized for treatment and post-exposure prophylaxis of COVID-19 in certain settings in the US, 18, 19 and for treatment and prevention of COVID-19 in other jurisdictions (known as Ronapreve TM outside of 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) preprint

The copyright holder for this this version posted November 16, 2021. ;  https://doi.org/10.1101/2021.11.10.21265889 doi: medRxiv preprint Page 5 US). 20 This study evaluated the safety, tolerability, and efficacy of monthly dosing of subcutaneous (SC) REGEN-COV in uninfected individuals.

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This phase 1, double-blind, placebo-controlled, study was conducted at 7 sites in the US (clinicaltrials.gov identifier, NCT04519437). The study was comprised of a screening/baseline period (up to 7 days), a treatment period (up to 24 weeks), and a follow-up period (28 weeks) (Supplementary Figure 1) . Subjects underwent an endof-treatment period visit 1 month after their final dose of study drug, before entering the 28-week follow-up period leading to an end of study visit. As of the data cut-off of May 21, 2021, all eligible subjects had completed the end-of-treatment visit after receipt of up to 6 doses of study drug; follow-up was ongoing, with not all subjects having completed the entire study. The rationale for 1200 mg SC dose selection and methods for dose administration are provided in the Supplementary Appendix.

Eligible subjects were uninfected adult volunteers, aged 18-90 years, who were healthy or had chronic but stable medical conditions, without signs/symptoms suggestive of COVID-19, and who were confirmed to be SARS-CoV-2 negative by central lab reverse transcription polymerase chain reaction (RT-PCR) of nasopharyngeal swab ≤ 72 hours of randomization. While in the treatment period, subjects who met any of the following criteria were discontinued from study drug and were moved into the follow-up period: tested positive for SARS-CoV-2, developed symptomatic COVID-19, experienced an adverse event (AE) that led to study drug discontinuation, received a dose of an investigational COVID-19 vaccine, or were unblinded per protocol to receive a COVID-19 vaccine. A full list of inclusion and . 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) preprint 

Subjects who elected to receive COVID-19 vaccination were discontinued from study drug and entered follow-up. Handling of COVID-19 vaccination during the study is described in the Supplementary Appendix.

The primary endpoints were to assess the incidence of AEs of special interest (AESIs), defined as grade 

Study oversight is described in the Supplementary Appendix.

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Baseline characteristics were balanced between the REGEN-COV and placebo groups. The overall median age was 48 years, 44.9% of subjects were female, 10% of subjects identified as African American, and 23.4% identified as Hispanic or Latino ( Table 1 ). There were 6 (0.6%) subjects who tested positive for SARS-CoV-2 via a centralized RT-PCR assay at baseline who had previously tested negative at screening with a local test; these subjects received 1 dose of study drug prior to the availability of the RT-PCR result from the central lab and were discontinued from additional doses of study drug and excluded from efficacy analyses but continued to be followed for safety. Subjects were included in the study regardless of SARS-CoV-2 antibody serostatus. At baseline, 825 (85.1%) subjects were seronegative for both SARS-CoV-2 anti-spike and anti-nucleocapsid antibodies, 101 (10.4%) were seropositive for anti-spike and/or anti-nucleocapsid antibodies, and 43 (4.4%) were of borderline or unknown serostatus ( Table 1) . Medical history was comparable between the REGEN-COV and placebo groups with 20% of subjects reporting ≥ 1 medical condition considered high-risk for progression to severe COVID-19; 21-23 the most common of these were hypertension and asthma ( Table 1; Supplementary   Table 1 ).

COVID-19 (symptomatic SARS-CoV-2 infection) determination was made by the investigator based on clinical assessment. In a predefined exploratory analysis 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. (which was not certified by peer review) preprint Table 2 ). These COVID-19 cases were evenly distributed throughout the study (Supplementary Figure 2) .

Two additional subjects who previously received placebo developed COVID- In the REGEN-COV group, each of the 3 (0.4%) subjects who had COVID-19

reported as an AE were seronegative for SARS-CoV-2 antibodies at baseline and at the end-of-treatment period visit (Supplementary Table 3 ). Two of the 3 subjects were negative for SARS-CoV-2 infection as assessed by RT-PCR, and 1 did not have RT-PCR data analyzed. Thus, while counted as a breakthrough from the antibody treatment, none of these 3 patients had laboratory confirmation of infection with SARS-CoV-2. Among these 3 REGEN-COV recipients, symptom duration was . 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) preprint

The copyright holder for this this version posted November 16, 2021. ; https://doi.org/10.1101/2021.11.10.21265889 doi: medRxiv preprint Page 11 11, 16, and 18 days, and symptoms were mostly mild (Supplementary Table 3 Table 4 ); a listing of all subjects who experienced the AE of COVID-19, including serologic and/or PCR confirmation, is provided in Supplementary Table 3 .

Conversion from SARS-CoV-2 anti-nucleocapsid seronegative to seropositive was used to assess the incidence of SARS-CoV-2 infection during the study. Of subjects who were seronegative for anti-spike or anti-nucleocapsid protein (anti-spike immunoglobulin [Ig]G, anti-spike IgA, or anti-nucleocapsid IgG) at baseline, 0/617 (0%) of REGEN-COV recipients were seropositive for anti-nucleocapsid protein (antinucleocapsid IgG) compared to 20/208 (9.6%) of placebo recipients at the end-oftreatment period visit, with a 100% risk reduction for anti-SARS-CoV-2 seroconversion, odds ratio: 0.00 (95% CI, 0.00-0.05) (Supplementary Table 5 ). 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. Table 5 ).

Over the 6-month treatment period, there were no AESIs (defined as grade 

In this multi-dose study, ISRs were experienced by 266/729 (36.5%) REGEN-COV recipients and 40/240 (16.7%) placebo recipients during the 6-month treatment period ( Table 2 ). All ISRs for REGEN-COV and placebo were mild (grade 1; 28.9% . 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) preprint Table 9 ). Across all 7 study sites combined, the rate of REGEN-COV ISRs was stable from dose 1 through 4 (~13% per dose) and was higher with dose 5 and 6 (~19% per dose) (Supplementary Figure 3A) . However, an imbalance in ISR rates was observed between study sites, with the overall incidence being driven by 2 outlier Figure 3C) .

. 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) preprint Table 12 ). AEs post COVID-19 vaccination were all grade 1-2, except for a single grade 3 event in a subject previously dosed with REGEN-COV; this grade 3 event of brain mass frontal lobe was assessed as not related to study drug (Supplementary Table 12 ).

PK analysis showed that concentrations of casirivimab and imdevimab in serum reached steady-state following the third dose of REGEN-COV and were maintained throughout the 6-month treatment period. Concentrations 28 days after the first dose of REGEN-COV were 32.7 mg/L for casirivimab and 24.8 mg/L for imdevimab, with accumulation ratios (ratio of concentrations 28 days after the sixth over the first dose) of 2.08-and 1.98-fold after 6 monthly doses, respectively (Figure 2) . Notably, in the 3 REGEN-COV recipients who reported COVID-19 symptoms, serum . 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) preprint We also examined whether repeat dosing would be associated with the formation of ADAs against either casirivimab or imdevimab, and whether these ADAs would impact circulating levels of drug. Casirivimab and imdevimab both showed low treatment-emergent immunogenicity, measured as ADAs in ≤ 5% of the population:

1.1% for anti-casirivimab and 5% for anti-imdevimab. Approximately 4% of subjects had pre-existing ADAs against casirivimab (3.1%) and imdevimab (3.9%) ( Table 3) .

ADAs did not appear to impact circulating levels of study drug, as concentrations of casirivimab and imdevimab were comparable between subjects with positive and negative ADA results (Supplementary Figure 4) .

. 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. This is the first study to investigate monthly dosing of SC administered REGEN-COV. Results from this study show that REGEN-COV is well-tolerated, and extend the findings of the household contact prevention study 17 by showing that monthly REGEN-COV prevents COVID-19 over a 6-month period. In a predefined exploratory efficacy analysis, REGEN-COV treatment resulted in a 92.4% RRR in presumptive COVID-19 versus placebo and a 100% RRR in laboratory-confirmed COVID-19. Although an assessment of efficacy was not the primary purpose of the study, the RRR for the development of COVID-19 seen in subjects treated with REGEN-COV is striking, and similar to the risk reduction seen in the vaccine trials. [30] [31] [32] [33] The overall number of COVID-19 events observed in this trial is similar to that seen in the recent PROVENT trial assessing pre-exposure prophylaxis of COVID-19 with another monoclonal antibody combination, AZD7442, which observed a 77% RRR with 25 COVID-19 cases in total during a 6-month treatment period. 34 . 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) preprint Importantly, in our trial, the placebo events were evenly distributed over 6 months, allowing us to demonstrate consistent efficacy across the entire treatment period. In contrast, in the PROVENT study, almost all of the placebo events occurred within the first 3 months of the 6-month trial, limiting the interpretation of efficacy assessments beyond 3 months.

Results of this study also demonstrate a significant reduction in antinucleocapsid IgG seroconversion among REGEN-COV treated subjects over the 6month course of therapy. The production of SARS-CoV-2 anti-nucleocapsid IgG antibodies, as assessed by seroconversion from a seronegative status at baseline to a seropositive status, was considered a proxy of SARS-CoV-2 infection. There was a 9.6% seroconversion rate among placebo recipients compared to the absence of seroconversion (0%) among those who received REGEN-COV, suggesting that REGEN-COV is also effective in preventing asymptomatic SARS-CoV-2 infection when given as chronic treatment for pre-exposure prophylaxis of COVID-19. This finding is particularly impactful for immunocompromised individuals and in the context of long-term care facilities, such as nursing homes, where protection against asymptomatic infection could reduce viral transmission and potentially decrease overall morbidity and mortality in these vulnerable populations. [35] [36] [37] Multiple dose administration of REGEN-COV was well-tolerated. Compared to placebo, REGEN-COV treatment was associated with a slightly higher frequency of ISRs. The overall rate of ISRs with REGEN-COV was ~13% per dose, and 36.5% across all 6 doses combined. However, there was significant variability in the ISR rate between sites, with 2 outlier sites driving the incidence. A previous phase 3 study assessing the efficacy of REGEN-COV 1200 mg as post-exposure prophylaxis . 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) preprint has shown an ISR rate of 4% after a single SC dose. 17 This is consistent with the reported ISR rate observed at 5 of the 7 sites in this study (~6% per dose); however, 2 sites exhibited disproportionately higher ISR rates of 19-34% and 17-54% per dose, respectively. All ISRs were mild to moderate in severity (grade 1-2) and the incidence and severity of ISRs did not substantially increase with repeat dosing.

There were no grade A potential limitation of this study was that regular RT-PCR testing was not performed in all participants who presented with a clinical syndrome compatible with COVID-19. However, when only considering laboratory confirmed SARS-CoV-2 infection, REGEN-COV showed a 100% RRR in the development of COVID-19. The discrepancy could imply that these subjects had illnesses that were not due to SARS-CoV-2, or that sample collection was not close enough to symptom onset.

An additional limitation of this study is that it was conducted before the emergence of several SARS-CoV-2 variants. However, extensive non-clinical testing has demonstrated that REGEN-COV retains its neutralization capacity against all clinically relevant viral variants tested to date, including beta, gamma, epsilon, and delta variants. 10,13

Although it should not be deemed an appropriate substitute for vaccination in immunocompetent individuals, the efficacy and safety profile of REGEN-COV demonstrated in this study strongly support that REGEN-COV should be used for chronic prevention of COVID-19 in individuals not expected to mount a sufficient . 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) preprint immune response to vaccination.

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The authors would like to thank the participants who volunteered for the study; the investigators involved in this study; Kaitlyn Scacalossi, PhD, and Caryn Trbovic, PhD, from Regeneron Pharmaceuticals for medical writing support; and Prime, Knutsford, UK, for formatting and copy-editing suggestions.

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Baseline SARS-CoV-2 RT-PCR result, n (%)

Baseline anti-SARS-CoV-2 serology result, n (%) a

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) preprintThe copyright holder for this this version posted November 16, 2021 Treatment of COVID-19. 2020. at https://www.fda.gov/news-events/pressannouncements/coronavirus-covid-19-update-fda-authorizes-monoclonal-antibodytreatment-covid-19.)

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The copyright holder for this this version posted November 16, 2021. ; https://doi.org/10.1101/2021.11.10.21265889 doi: medRxiv preprint 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) preprint . 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. . 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) preprintThe copyright holder for this this version posted November 16, 2021. ; https://doi.org/10.1101/2021.11.10.21265889 doi: medRxiv preprint