Abstract: medRxiv preprint doi: https://doi.org/10.1101/2021.11.10.21265889; this version posted November 16, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Repeat Subcutaneous Administration of REGEN-COV® in Adults is Well-Tolerated and Prevents the Occurrence of COVID-19 Flonza Isa,1 Eduardo Forleo-Neto,1 Jonathan Meyer,1 Wenjun Zheng,1 Scott Rasmussen,2 Danielle Armas,3 Masaru Oshita,4 Cynthia Brinson,5 Steven Folkerth,6 Lori Faria,1 Ingeborg Heirman,1 Neena Sarkar,1 Bret J. Musser,1 Shikha Bansal,1 Meagan P. O’Brien,1 Kenneth C. Turner,1 Samit Ganguly,1 Adnan Mahmood,1 Ajla Dupljak,1 Andrea T. Hooper,1 Jennifer D. Hamilton,1 Yunji Kim,1 Bari Kowal,1 Yuhwen Soo,1 Gregory P. Geba,1 Leah Lipsich,1 Ned Braunstein,1 George D. Yancopoulos,1 David M. Weinreich,1 Gary A. Herman,1 the COVID-19 Multi-dose Trial Team 1 Regeneron Pharmaceuticals, Inc., Tarrytown, NY; 2Celerion, Lincoln, NE; 3Celerion, Tempe, AZ; 4Benchmark Research, Sacramento, CA; 5Central Texas Clinical Research, LLC, Austin, TX; 6Midwest Clinical Research Center, LLC, Dayton, OH. Correspondence to: Flonza Isa, MD; Email: flonza.isa@regeneron.com Page 1 NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2021.11.10.21265889; this version posted November 16, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Abstract Background: Data show that a single dose of casirivimab and imdevimab (REGENCOV®) 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 COVID19 or SARS-CoV-2 seroconversion. Results: In total, 969 subjects were treated. Repeat monthly dosing of SC REGENCOV 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. Page 2 medRxiv preprint doi: https://doi.org/10.1101/2021.11.10.21265889; this version..