“A Prophylactic Arrow in the Covid-19 Quiver?” – Use of Ensitrelvir as Covid-19 Postexposure Prophylaxis

Reviewed by: David Cluck, PharmD; East Tennessee State University

Ensitrelvir is a noncovalent, nonpeptide targeting the main protease (Mpro) or 3C-like protease (3CLpro) – a cysteine protease pivotal for viral replication of SARS-CoV-2.1 In the SCORPIO-PEP study (Stopping Covid-19 Progression with Early Protease Inhibi­tor Treatment for Post-Exposure Prophylaxis), Hayden and colleagues sought to determine whether ensitrelvir would be effi­cacious as postexposure prophylaxis in persons exposed to SARS-CoV-2 in a household setting.2 Patients who were SARS-CoV-2–negative on local diagnostic testing but were household contacts of a patient with Covid-19 were randomized 1:1 to receive either ensitrelvir (375 mg on day 1 and 125 mg daily on days 2 through 5) or placebo within 72 hours after symptom onset in the index patient. The primary end point was Covid-19 (defined by a central laboratory–confirmed positive reverse-transcriptase–polymerase- chain-reaction assay and the presence of at least 1 of 14 prespecified Covid-19 symptoms lasting ≥48 hours) by day 10 in a household contact in the modified intention- to-treat population. The modified intention-to-treat population, defined as study participants who underwent randomization, had a central laboratory–confirmed negative RT-PCR test for SARS-CoV-2 at baseline, and received at least one dose of the trial drug or placebo, included 1030 participants in the ensi­trelvir group and 1011 in the placebo group. The incidence of Covid-19 was lower in the ensitrelvir group than in the placebo group (2.9% vs. 9.0%; risk ratio, 0.33; 95% confidence interval [CI], 0.22 to 0.49; P<0.001) corresponding to a 67% relative risk reduction. A subgroup analysis among participants with at least one risk factor for severe Covid-19 had a 76% relative risk reduction. The findings are limited by a low secondary attack rate in the placebo arm when compared to historical data, precautions taken by participants such as masking and social distancing and concomitant use of antiviral therapy in index patients.  

This study demonstrated that ensitrelvir administered to household contacts of a patient with Covid-19 within 72 hours after symptom onset in the index patient was effective in preventing Covid-19. This is notable as previous studies with other Covid-19 antivirals failed to show benefit in this scenario.3,4 Notably, while ensitrelvir is now FDA-approved, it is only for use as PEP in patients presenting within 72 hours of exposure.

References:

  1. Kuroda T, Nobori H, Fukao K, et al. Efficacy comparison of 3CL protease in­hibitors ensitrelvir and nirmatrelvir against SARS-CoV-2 in vitro and in vivo. J Antimi­crob Chemother 2023; 78: 946-52.
  2. Hayden FG, Shinkai M, Clark TW, Luetkemeyer AF, Sax PE, Hanage WP, Gebo KA, Ikematsu H, Izumikawa K, Fukushi A, Kezbor S, Sakaguchi H, Lacey S, Ichihashi G, Ohmagari N, Uehara T; SCORPIO-PEP Study Team. Ensitrelvir for Covid-19 Postexposure Prophylaxis in Household Contacts. N Engl J Med. 2026;394(19):1905-1915. 
  3. Hammond J, Yunis C, Fountaine RJ, Luscan G, Burr AM, Zhang W, Wisemandle W, Soares H, Baniecki ML, Hendrick VM, Kalfov V, Pypstra R, Rusnak JM. Oral Nirmatrelvir-Ritonavir as Postexposure Prophylaxis for Covid-19. N Engl J Med. 2024;391(3):224-234. 
  4. Alpizar SA, Accini J, Anderson DC, Eysa B, Medina-Piñón I, Ohmagari N, Ostrovskyy MM, Aggrey-Amable A, Beck K, Byrne D, Grayson S, Hwang PMT, Lonchar JD, Strizki J, Xu Y, Paschke A, De Anda CS, Sears PS; MOVe-AHEAD study group. Molnupiravir for intra-household prevention of COVID-19: The MOVe-AHEAD randomized, placebo-controlled trial. J Infect. 2023 Nov;87(5):392-402.