A Randomized Phase 2/3 Study of Ensitrelvir, a Novel Oral SARS-CoV-2 3C-like Protease Inhibitor, in Japanese Patients With Mild-to-Moderate COVID-19 or Asymptomatic SARS-CoV-2 Infection: Results of the Phase 2a Part

Mukae et al., medRxiv, doi:10.1101/2022.05.17.22275027, jRCT2031210350, May 2022
Change in viral titer, 2.. 45% primary improvement lower risk ← → higher risk Change in viral titer, 1.. 36% primary Time to viral-, 125mg 45% Time to viral-, 250mg 44% Viral clearance, 250m.. 54% Viral clearance, 125m.. -10% Viral clearance, 250.. b 80% Viral clearance, 125.. b 54% Viral clearance, 250.. c 54% Viral clearance, 125.. c 90% Viral clearance, 250.. d 80% Viral clearance, 125.. d 63% Viral clearance, 250.. e 9% Viral clearance, 125.. e -10% Ensitrelvir  Mukae et al.  EARLY TREATMENT RCT Is early treatment with ensitrelvir beneficial for COVID-19? Double-blind RCT 69 patients in Japan (September 2021 - January 2022) Improved viral clearance with ensitrelvir (p=0.0025) c19early.org Mukae et al., medRxiv, May 2022 0 0.5 1 1.5 2+ RR
49th treatment shown to reduce risk in July 2023, now with p = 0.015 from 8 studies.
Lower risk for hospitalization, recovery, cases, and viral clearance.
No treatment is 100% effective. Protocols combine treatments.
6,300+ studies for 210+ treatments. c19early.org
Meta Analysis
RCT 69 patients in in Japan, showing faster viral clearance with ensitrelvir. 5-day ensitrelvir (375mg on day 1 followed by 125 mg daily or 750mg on day 1 followed by 250mg daily).
Standard of Care (SOC) for COVID-19 in the study country, Japan, is very poor with very low average efficacy for approved treatments1. Only expensive, high-profit treatments were approved for early treatment. Low-cost treatments were excluded, reducing the probability of early treatment due to access and cost barriers, and eliminating complementary and synergistic benefits seen with many low-cost treatments.
Important missing comments or errors? Let us know.
relative change in viral titer, 45.2% better, RR 0.55, p = 0.002, treatment mean 2.81 (±1.21) n=14, control mean 1.54 (±0.74) n=14, day 4, 250mg, primary outcome.
relative change in viral titer, 36.4% better, RR 0.64, p = 0.048, treatment mean 2.42 (±1.42) n=15, control mean 1.54 (±0.74) n=14, day 4, 125mg, primary outcome.
time to viral-, 44.8% lower, relative time 0.55, p = 0.02, treatment 15, control 14, 125mg.
time to viral-, 43.6% lower, relative time 0.56, p = 0.02, treatment 13, control 14, 250mg.
risk of no viral clearance, 54.2% lower, RR 0.46, p = 0.59, treatment 1 of 12 (8.3%), control 2 of 11 (18.2%), NNT 10, day 14, 250mg, Figure S1.
risk of no viral clearance, 10.0% higher, RR 1.10, p = 1.00, treatment 3 of 15 (20.0%), control 2 of 11 (18.2%), day 14, 125mg, Figure S1.
risk of no viral clearance, 80.0% lower, RR 0.20, p = 0.48, treatment 0 of 13 (0.0%), control 2 of 13 (15.4%), NNT 6.5, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), day 9, 250mg, Figure S1.
risk of no viral clearance, 53.6% lower, RR 0.46, p = 0.60, treatment 1 of 14 (7.1%), control 2 of 13 (15.4%), NNT 12, day 9, 125mg, Figure S1.
risk of no viral clearance, 53.6% lower, RR 0.46, p = 0.38, treatment 2 of 14 (14.3%), control 4 of 13 (30.8%), NNT 6.1, day 6, 250mg, Figure S1.
risk of no viral clearance, 89.6% lower, RR 0.10, p = 0.03, treatment 0 of 15 (0.0%), control 4 of 13 (30.8%), NNT 3.2, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), day 6, 125mg, Figure S1.
risk of no viral clearance, 80.0% lower, RR 0.20, p = 0.006, treatment 2 of 14 (14.3%), control 10 of 14 (71.4%), NNT 1.8, day 4, 250mg, Figure S1.
risk of no viral clearance, 62.7% lower, RR 0.37, p = 0.03, treatment 4 of 15 (26.7%), control 10 of 14 (71.4%), NNT 2.2, day 4, 125mg, Figure S1.
risk of no viral clearance, 9.1% lower, RR 0.91, p = 1.00, treatment 10 of 14 (71.4%), control 11 of 14 (78.6%), NNT 14, day 2, 250mg, Figure S1.
risk of no viral clearance, 10.3% higher, RR 1.10, p = 0.65, treatment 13 of 15 (86.7%), control 11 of 14 (78.6%), day 2, 125mg, Figure S1.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Mukae et al., 17 May 2022, Double Blind Randomized Controlled Trial, placebo-controlled, Japan, preprint, 13 authors, study period 28 September, 2021 - 1 January, 2022, trial jRCT2031210350. Contact: takeki.uehara@shionogi.co.jp.
$0 $500 $1,000+ Efficacy vs. cost for COVID-19 treatment protocols c19early.org December 2025 Japan United Kingdom Russia USA Sudan Angola Colombia Kenya Mozambique Vietnam Peru Philippines China Uzbekistan Nepal Ethiopia Iran Ghana Mexico South Korea Germany Bangladesh Saudi Arabia Algeria Morocco Yemen Poland India DR Congo Madagascar Thailand Uganda Venezuela Nigeria Egypt Bolivia Taiwan Zambia Fiji Bosnia-Herzegovina Ukraine Côte d'Ivoire Bulgaria Greece Slovakia Singapore Iceland New Zealand Czechia Mongolia Israel Trinidad and Tobago Hong Kong North Macedonia Belarus Qatar Panama Serbia CAR Japan favored high-profit treatments.The average efficacy of treatments was very low.High-cost protocols reduce early treatment, andforgo complementary/synergistic benefits. More effective More expensive 75% 50% 25% ≤0%
$0 $500 $1,000+ Efficacy vs. cost for COVID-19treatment protocols worldwide c19early.org December 2025 Japan United Kingdom Russia USA Sudan Angola Colombia Kenya Mozambique Vietnam Peru Philippines China Uzbekistan Nepal Ethiopia Iran Ghana Mexico South Korea Germany Bangladesh Saudi Arabia Algeria Morocco Yemen Poland India DR Congo Madagascar Thailand Uganda Venezuela Nigeria Egypt Bolivia Taiwan Zambia Fiji Bosnia-Herzegovina Ukraine Côte d'Ivoire Eritrea Bulgaria Greece Slovakia Singapore New Zealand Malawi Czechia Mongolia Israel Trinidad and Tobago North Macedonia Belarus Qatar Panama Serbia Syria Japan favored high-profit treatments.The average efficacy was very low.High-cost protocols reduce early treatment,and forgo complementary/synergistic benefits. More effective More expensive 75% 50% 25% ≤0%
A Randomized Phase 2/3 Study of Ensitrelvir, a Novel Oral SARS-CoV-2 3C-like Protease Inhibitor, in Japanese Patients With Mild-to-Moderate COVID-19 or Asymptomatic SARS-CoV-2 Infection: Results of the Phase 2a Part
Hiroshi Mukae, Hiroshi Yotsuyanagi, Norio Ohmagari, Yohei Doi, Takumi Imamura, Takuhiro Sonoyama, Takahiro Fukuhara, Genki Ichihashi, Takao Sanaki, Keiko Baba, Yosuke Takeda, Yuko Tsuge, Takeki Uehara
doi:10.1101/2022.05.17.22275027
All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
References
Beigel, Tomashek, Dodd, Mehta, Zingman et al., Remdesivir for the treatment of COVID-19 -Final report, N Engl J Med
Bernal, Da Silva, Musungaie, Kovalchuk, Gonzalez et al., Molnupiravir for oral treatment of COVID-19 in nonhospitalized patients, N Engl J Med
Brown, Vostok, Johnson, Burns, Gharpure et al., Outbreak of SARS-CoV-2 infections, including COVID-19 vaccine breakthrough infections, associated with large public gatherings -Barnstable County, Massachusetts, MMWR Morb Mortal Wkly Rep
Clark, Jit, Warren-Gash, Guthrie, Wang et al., Global, regional, and national estimates of the population at increased risk of severe COVID-19 due to underlying health conditions in 2020: a modelling study, Lancet Glob Health
Fischer, Eron, Holman, Cohen, Fang et al., A phase 2a clinical trial of molnupiravir in patients with COVID-19 shows accelerated SARS-CoV-2 RNA clearance and elimination of infectious virus, Sci Transl Med
Folgueira, Luczkowiak, Lasala, Pérez-Rivilla, Delgado, Prolonged SARS-CoV-2 cell culture replication in respiratory samples from patients with severe COVID-19, Clin Microbiol Infect
Gupta, Gonzalez-Rojas, Juarez, Casal, Moya et al., Early treatment for COVID-19 with SARS-CoV-2 neutralizing antibody sotrovimab, N Engl J Med
Hammond, Leister-Tebbe, Gardner, Abreu, Wisemandle et al., Oral nirmatrelvir for high-risk, nonhospitalized adults with COVID-19, N Engl J Med
He, Hu, Huang, Wang, Zhang et al., Potential of coronavirus 3C-like protease inhibitors for the development of new anti-SARS-CoV-2 drugs: insights from structures of protease and inhibitors, Int J Antimicrob Agents
Mckimm-Breschkin, Hay, Cao, Cox, Dunning et al., COVID-19, influenza and RSV: surveillance-informed prevention and treatment -meeting report from an isirv-WHO virtual conference, Antiviral Res
Oran, Topol, The proportion of SARS-CoV-2 infections that are asymptomatic: a systematic review, Ann Intern Med
Singanayagam, Patel, Charlett, Bernal, Saliba et al., Duration of infectiousness and correlation with RT-PCR cycle threshold values in cases of COVID-19, England, January to, Euro Surveill
Unoh, Uehara, Nakahara, Nobori, Yamatsu et al., Discovery of S-217622, a non-covalent oral SARS-CoV-2 3CL protease inhibitor clinical candidate for treating COVID-19, J Med Chem, doi:10.1021/acs.jmedchem.2c00117
Van Kampen, Van De Vijver, Fraaij, Haagmans, Lamers et al., Duration and key determinants of infectious virus shedding in hospitalized patients with coronavirus disease-2019 (COVID-19), Nat Commun
Weinreich, Sivapalasingam, Norton, Ali, Gao et al., REGEN-COV antibody combination and outcomes in outpatients with COVID-19, N Engl J Med
DOI record: { "DOI": "10.1101/2022.05.17.22275027", "URL": "http://dx.doi.org/10.1101/2022.05.17.22275027", "abstract": "<jats:title>ABSTRACT</jats:title><jats:p>For the treatment of coronavirus disease 2019 (COVID-19), antiviral agents that can achieve rapid severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reduction are warranted. This double-blind, phase 2a part of a phase 2/3 study assessed the efficacy and safety of ensitrelvir, a novel oral SARS-CoV-2 3C-like protease inhibitor, in Japanese patients with mild-to-moderate COVID-19 or asymptomatic SARS-CoV-2 infection. Sixty-nine patients enrolled from 56 sites were randomized (1:1:1) to orally receive 5-day ensitrelvir fumaric acid (375 mg on day 1 followed by 125 mg daily or 750 mg on day 1 followed by 250 mg daily) or placebo and followed up until day 28. The primary outcome was change from baseline in SARS-CoV-2 viral titer. A total of 16, 14, and 17 patients in the ensitrelvir 125 mg, ensitrelvir 250 mg, and placebo groups, respectively, were included in the intention-to-treat population (mean age: 38.8, 40.4, and 38.0 years, respectively). On day 4, the change from baseline in SARS-CoV-2 viral titer (log<jats:sub>10</jats:sub> 50% tissue culture infectious dose/mL) in patients with positive viral titer and viral RNA at baseline was greater with ensitrelvir 125 mg (mean [standard deviation], −2.42 [1.42]; <jats:italic>P</jats:italic> = 0.0712) and 250 mg (−2.81 [1.21]; <jats:italic>P</jats:italic> = 0.0083) versus placebo (−1.54 [0.74]), and ensitrelvir treatment reduced SARS-CoV-2 RNA by −1.4 to −1.5 log<jats:sub>10</jats:sub> copies/mL versus placebo. All adverse events were mild to moderate. Ensitrelvir treatment demonstrated rapid SARS-CoV-2 clearance and was well tolerated in patients with mild-to-moderate COVID-19 or asymptomatic SARS-CoV-2 infection (Japan Registry of Clinical Trials identifier: jRCT2031210350).</jats:p>", "accepted": { "date-parts": [ [ 2022, 5, 17 ] ] }, "author": [ { "affiliation": [], "family": "Mukae", "given": "Hiroshi", "sequence": "first" }, { "affiliation": [], "family": "Yotsuyanagi", "given": "Hiroshi", "sequence": "additional" }, { "affiliation": [], "family": "Ohmagari", "given": "Norio", "sequence": "additional" }, { "affiliation": [], "family": "Doi", "given": "Yohei", "sequence": "additional" }, { "affiliation": [], "family": "Imamura", "given": "Takumi", "sequence": "additional" }, { "affiliation": [], "family": "Sonoyama", "given": "Takuhiro", "sequence": "additional" }, { "affiliation": [], "family": "Fukuhara", "given": "Takahiro", "sequence": "additional" }, { "affiliation": [], "family": "Ichihashi", "given": "Genki", "sequence": "additional" }, { "affiliation": [], "family": "Sanaki", "given": "Takao", "sequence": "additional" }, { "affiliation": [], "family": "Baba", "given": "Keiko", "sequence": "additional" }, { "affiliation": [], "family": "Takeda", "given": "Yosuke", "sequence": "additional" }, { "affiliation": [], "family": "Tsuge", "given": "Yuko", "sequence": "additional" }, { "affiliation": [], "family": "Uehara", "given": "Takeki", "sequence": "additional" } ], "container-title": [], "content-domain": { "crossmark-restriction": false, "domain": [] }, "created": { "date-parts": [ [ 2022, 5, 23 ] ], "date-time": "2022-05-23T18:33:08Z", "timestamp": 1653330788000 }, "deposited": { "date-parts": [ [ 2022, 5, 23 ] ], "date-time": "2022-05-23T18:44:59Z", "timestamp": 1653331499000 }, "group-title": "Infectious Diseases (except HIV/AIDS)", "indexed": { "date-parts": [ [ 2023, 1, 14 ] ], "date-time": "2023-01-14T11:14:42Z", "timestamp": 1673694882703 }, "institution": [ { "name": "medRxiv" } ], "is-referenced-by-count": 3, "issued": { "date-parts": [ [ 2022, 5, 17 ] ] }, "link": [ { "URL": "https://syndication.highwire.org/content/doi/10.1101/2022.05.17.22275027", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "246", "original-title": [], "posted": { "date-parts": [ [ 2022, 5, 17 ] ] }, "prefix": "10.1101", "published": { "date-parts": [ [ 2022, 5, 17 ] ] }, "publisher": "Cold Spring Harbor Laboratory", "reference": [ { "DOI": "10.7326/M20-6976", "article-title": "The proportion of SARS-CoV-2 infections that are asymptomatic: a systematic review", "doi-asserted-by": "crossref", "first-page": "655", "journal-title": "Ann Intern Med", "key": "2022052309232260000_2022.05.17.22275027v1.1", "volume": "174", "year": "2021" }, { "DOI": "10.1016/S2214-109X(20)30264-3", "article-title": "Global, regional, and national estimates of the population at increased risk of severe COVID-19 due to underlying health conditions in 2020: a modelling study", "doi-asserted-by": "crossref", "first-page": "e1003", "journal-title": "Lancet Glob Health", "key": "2022052309232260000_2022.05.17.22275027v1.2", "volume": "8", "year": "2020" }, { "DOI": "10.2807/1560-7917.ES.2020.25.32.2001483", "doi-asserted-by": "publisher", "key": "2022052309232260000_2022.05.17.22275027v1.3" }, { "DOI": "10.1016/j.cmi.2021.02.014", "article-title": "Prolonged SARS-CoV-2 cell culture replication in respiratory samples from patients with severe COVID-19", "doi-asserted-by": "crossref", "first-page": "886", "journal-title": "Clin Microbiol Infect", "key": "2022052309232260000_2022.05.17.22275027v1.4", "volume": "27", "year": "2021" }, { "DOI": "10.1038/s41467-020-20568-4", "doi-asserted-by": "publisher", "key": "2022052309232260000_2022.05.17.22275027v1.5" }, { "DOI": "10.15585/mmwr.mm7031e2", "article-title": "Outbreak of SARS-CoV-2 infections, including COVID-19 vaccine breakthrough infections, associated with large public gatherings - Barnstable County, Massachusetts, July 2021", "doi-asserted-by": "crossref", "first-page": "1059", "journal-title": "MMWR Morb Mortal Wkly Rep", "key": "2022052309232260000_2022.05.17.22275027v1.6", "volume": "70", "year": "2021" }, { "DOI": "10.1056/NEJMoa2116044", "article-title": "Molnupiravir for oral treatment of COVID-19 in nonhospitalized patients", "doi-asserted-by": "crossref", "first-page": "509", "journal-title": "N Engl J Med", "key": "2022052309232260000_2022.05.17.22275027v1.7", "volume": "386", "year": "2022" }, { "DOI": "10.1056/NEJMoa2118542", "article-title": "Oral nirmatrelvir for high-risk, nonhospitalized adults with COVID-19", "doi-asserted-by": "crossref", "first-page": "1397", "journal-title": "N Engl J Med", "key": "2022052309232260000_2022.05.17.22275027v1.8", "volume": "386", "year": "2022" }, { "DOI": "10.1056/NEJMoa2107934", "article-title": "Early treatment for COVID-19 with SARS-CoV-2 neutralizing antibody sotrovimab", "doi-asserted-by": "crossref", "first-page": "1941", "journal-title": "N Engl J Med", "key": "2022052309232260000_2022.05.17.22275027v1.9", "volume": "385", "year": "2021" }, { "DOI": "10.1056/nejmoa2108163", "doi-asserted-by": "publisher", "key": "2022052309232260000_2022.05.17.22275027v1.10" }, { "DOI": "10.1056/NEJMoa2007764", "doi-asserted-by": "publisher", "key": "2022052309232260000_2022.05.17.22275027v1.11" }, { "DOI": "10.1101/2022.01.26.477782", "doi-asserted-by": "crossref", "key": "2022052309232260000_2022.05.17.22275027v1.12", "unstructured": "Unoh Y , Uehara S , Nakahara K , Nobori H , Yamatsu Y , Yamamoto S , Maruyama Y , Taoda Y , Kasamatsu K , Suto T , Kouki K , Nakahashi A , Kawashima S , Sanaki T , Toba S , Uemura K , Mizutare T , Ando S , Sasaki M , Orba Y , Sawa H , Sato A , Sato T , Kato T , Tachibana Y. 2022. Discovery of S-217622, a non-covalent oral SARS-CoV-2 3CL protease inhibitor clinical candidate for treating COVID-19. J Med Chem https://doi.org/10.1021/acs.jmedchem.2c00117." }, { "DOI": "10.1016/j.ijantimicag.2020.106055", "doi-asserted-by": "publisher", "key": "2022052309232260000_2022.05.17.22275027v1.13" }, { "DOI": "10.1016/j.antiviral.2021.105227", "article-title": "COVID-19, influenza and RSV: surveillance-informed prevention and treatment - meeting report from an isirv-WHO virtual conference", "doi-asserted-by": "crossref", "first-page": "105227", "journal-title": "Antiviral Res", "key": "2022052309232260000_2022.05.17.22275027v1.14", "volume": "197", "year": "2022" }, { "DOI": "10.1126/scitranslmed.abl7430", "article-title": "A phase 2a clinical trial of molnupiravir in patients with COVID-19 shows accelerated SARS-CoV-2 RNA clearance and elimination of infectious virus", "doi-asserted-by": "crossref", "first-page": "eabl7430", "journal-title": "Sci Transl Med", "key": "2022052309232260000_2022.05.17.22275027v1.15", "volume": "14", "year": "2022" } ], "reference-count": 15, "references-count": 15, "relation": {}, "resource": { "primary": { "URL": "http://medrxiv.org/lookup/doi/10.1101/2022.05.17.22275027" } }, "score": 1, "short-title": [], "source": "Crossref", "subtitle": [], "subtype": "preprint", "title": "A Randomized Phase 2/3 Study of Ensitrelvir, a Novel Oral SARS-CoV-2 3C-like Protease Inhibitor, in Japanese Patients With Mild-to-Moderate COVID-19 or Asymptomatic SARS-CoV-2 Infection: Results of the Phase 2a Part", "type": "posted-content" }
Please send us corrections, updates, or comments. c19early involves the extraction of 200,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. IMA and WCH provide treatment protocols.
  or use drag and drop   
Submit    
Post
Share
@CovidAnalysis
FAQ
Public domain CC0 1.0