Ensitrelvir

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Ensitrelvir
Ensitrelvir.svg
Clinical data
Trade names Xocova
Other namesS-217622
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
  • JP: Rx-only [1]
Pharmacokinetic data
Elimination half-life 42–48 hours [2]
Identifiers
  • 1-(2,4,5-Trifluorobenzyl)-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-(6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-1,3,5-triazinane-2,4-dione
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
Chemical and physical data
Formula C22H17ClF3N9O2
Molar mass 531.88 g·mol−1
3D model (JSmol)
  • Cn1cnc(CN2C(=O)N(Cc3cc(F)c(F)cc3F)C(=N\c3cc4cn(C)nc4cc3Cl)\NC2=O)n1
  • InChI=1S/C22H17ClF3N9O2/c1-32-7-12-4-18(13(23)5-17(12)30-32)28-20-29-21(36)35(9-19-27-10-33(2)31-19)22(37)34(20)8-11-3-15(25)16(26)6-14(11)24/h3-7,10H,8-9H2,1-2H3,(H,28,29,36)
  • Key:QMPBBNUOBOFBFS-UHFFFAOYSA-N
Xocova in a Japanese blister pack Xocova.jpg
Xocova in a Japanese blister pack

Ensitrelvir, sold under the brand name Xocova is an antiviral medication used as a treatment for COVID-19. [3] [4] [5] [6] It was developed by Shionogi in partnership with Hokkaido University and acts as an orally active 3C-like protease inhibitor. [7] [8] It is taken by mouth. [9] [10] [11]

Contents

The most common adverse events include transient decreases in high-density lipoprotein and increased blood triglycerides. [9]

Medical uses

Ensitrelvir is indicated for the treatment of COVID-19. [9]

History

As of 2022, ensitrelvir had reached Phase III clinical trials. [12] The Japanese government is reportedly considering allowing Shionogi permission to apply for approval for medical use before the final steps of trials are completed, potentially speeding up the release for sale. This conditional early approval system has previously been used in Japan to accelerate the progression to market of other antiviral drugs targeting COVID-19, including remdesivir and molnupiravir. [13] In a study of 428 patients, viral load was reduced, but symptoms were not significantly reduced. [14]

In February 2022, the company sought emergency approval from regulators in Japan. [4] [14]

Shionogi announced they had reached a preliminary agreement to supply 1 million doses to the Japanese government once the drug is approved. The CEO said they could have capacity to make 10 million doses a year. [15]

Ensitrelvir may be effective in treating smell and taste loss from COVID-19 infection. In a 2023 study, the drug was associated with a 39% reduction in these symptoms. [16]

Society and culture

Ensitrelvir was approved for emergency use in Japan in November 2022, [9] [4] [5] before gaining full approval in March 2024. [1] It was approved in Singapore in November 2023. [17]

In April 2023, ensitrelvir was given a "Fast Track" designation from the US Food and Drug Administration. [18]

Names

Ensitrelvir is the international nonproprietary name (INN). [19]

Research

Ensitrelvir has been investigated for use as potential post-exposure prophylaxis (PEP) for SARS-CoV-2 infection. [20] [21] The SCORPIO-PEP trial, a global Phase 3 study, assessed the safety and efficacy of ensitrelvir in preventing symptomatic COVID-19 among household contacts of individuals with confirmed SARS-CoV-2 infection. [21] [22] [23] [24] Top-line results from this trial suggested that use of ensitrelvir as post-exposure prophylaxis may significantly reduce the risk of symptomatic COVID-19 infection in exposed household contacts compared to placebo. [25] [26] [27]

An April 2024 pre-clinical study in a mouse model investigating ensitrelvir demonstrated its potential use as a pre-exposure prophylactic (PrEP) against developing COVID-19. When administered 24 hours before viral exposure, a single dose of ensitrelvir significantly increased survival rates, inhibited weight loss, and suppressed viral replication in aged mice. [28]

A retrospective study conducted between November 2022 and July 2023 using a large Japanese health insurance database suggested that ensitrelvir may be effective in reducing hospitalization risk in outpatients at high risk for severe COVID-19. The study found a significantly lower risk of hospitalization and a reduced need for respiratory monitoring and oxygen therapy in the ensitrelvir group compared to the control group. [29] In addition, other clinical study shows that early ensitrelvir treatment resulted in rapid symptom relief and significant viral load reduction, with no adverse events, viral rebound, or PASC symptoms, demonstrating its potential efficacy and safety. [30]

In May 2024, Shionogi announced that in a phase 3 trial (SCORPIO-HR), ensitrelvir did not achieve its primary endpoint of a statistically significant reduction in the time to sustained resolution of 15 common COVID-19 symptoms compared to placebo. However, the drug did meet key secondary endpoints, including demonstrating a significant reduction in viral RNA levels, a shorter time to achieve the first negative infectious viral titer in nasal swabs compared to placebo, and a shorter resolution time of 6 symptoms. [31]

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References

  1. 1 2 "Japan health ministry approves Shionogi's COVID drug Xocova". NHK WORLD. 5 March 2024. Retrieved 6 March 2024.
  2. ↑ Shimizu R, Sonoyama T, Fukuhara T, Kuwata A, Matsuo Y, Kubota R (October 2022). "Safety, Tolerability, and Pharmacokinetics of the Novel Antiviral Agent Ensitrelvir Fumaric Acid, a SARS-CoV-2 3CL Protease Inhibitor, in Healthy Adults". Antimicrobial Agents and Chemotherapy . 66 (10): e0063222. doi:10.1128/aac.00632-22. PMC   9578392 . PMID   36094202.
  3. ↑ McCarthy MW (December 2022). "Ensitrelvir as a potential treatment for COVID-19". Expert Opinion on Pharmacotherapy. 23 (18): 1995–1998. doi:10.1080/14656566.2022.2146493. PMID   36350029. S2CID   253418404.
  4. 1 2 3 Fujikawa M (22 November 2022). "Japan Approves First Homegrown Covid-19 Antiviral Pill". The Wall Street Journal . Retrieved 28 November 2022.
  5. 1 2 "Shionogi's Covid antiviral lands first approval in Japan's new emergency approval pathway". Endpoints News. 22 November 2022. Retrieved 28 November 2022.
  6. ↑ "Xocova: Powerful New Japanese Pill for Coronavirus Treatment". BioPharma Media. February 2022.
  7. ↑ Unoh Y, Uehara S, Nakahara K, Nobori H, Yamatsu Y, Yamamoto S, et al. (May 2022). "Discovery of S-217622, a Noncovalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19". Journal of Medicinal Chemistry. 65 (9): 6499–6512. doi:10.1021/acs.jmedchem.2c00117. PMC   8982737 . PMID   35352927.
  8. ↑ "Shionogi presents positive Ph II/III results for COVID-19 antiviral S-217622". thepharmaletter.com. 31 January 2022.
  9. 1 2 3 4 "Xocova (Ensitrelvir Fumaric Acid) Tablets 125mg Approved in Japan for the Treatment of SARS-CoV-2 Infection, under the Emergency Regulatory Approval System". Shionogi (Press release). 22 November 2022. Retrieved 28 November 2022.
  10. ↑ "Shionogi's new COVID pill appears to ease omicron symptoms". Nikkei Asia. 21 December 2021.
  11. ↑ Uraki R, Kiso M, Iida S, Imai M, Takashita E, Kuroda M, et al. (IASO study team) (May 2022). "Characterization and antiviral susceptibility of SARS-CoV-2 Omicron/BA.2". Nature. 607 (7917): 119–127. Bibcode:2022Natur.607..119U. doi: 10.1038/s41586-022-04856-1 . PMC   10579982 . PMID   35576972. S2CID   248833104.
  12. ↑ Tyndall JD (May 2022). "S-217622, a 3CL Protease Inhibitor and Clinical Candidate for SARS-CoV-2". Journal of Medicinal Chemistry. 65 (9): 6496–6498. doi:10.1021/acs.jmedchem.2c00624. PMID   35507419. S2CID   248513467.
  13. ↑ "Japan to consider early approval for Shionogi COVID-19 pill". Japan Times. 8 February 2022.
  14. 1 2 "Japan's Shionogi seeks approval for COVID-19 pill". Reuters. 25 February 2022.
  15. ↑ "Japan's Shionogi signs government supply pact for pill to fight COVID". Reuters. 25 March 2022.
  16. ↑ Lenharo M (17 October 2023). "New pill helps COVID smell and taste loss fade quickly". Nature. doi:10.1038/d41586-023-03244-7. PMID   37853192. S2CID   264303912.
  17. ↑ "Shionogi reports data from Phase III portion of Covid-19 drug trial". Clinical Trials Arena. 12 February 2024. Retrieved 6 March 2024.
  18. ↑ Ducharme J (25 January 2024). "When Will We Get New COVID-19 Drugs?". Time. Retrieved 6 March 2024.
  19. ↑ World Health Organization (2022). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 88". WHO Drug Information. 36 (3): 89. hdl: 10665/363551 .
  20. ↑ Cosdon N (31 March 2023). "Ensitrelvir: A COVID-19 Antiviral That Remains Effective Against New Variants". ContagionLive. Retrieved 28 October 2023.
  21. 1 2 "Shionogi presses on with Xocova research following Japanese approval". The Pharma Letter . 16 February 2023. Retrieved 28 October 2023.
  22. ↑ "Studies Currently Enrolling". University of Kansas Medical Center. Archived from the original on 28 October 2023. Retrieved 28 October 2023. SCORPIO-PEP is a 28-day study to assess the prevention of COVID-19 infection in those who have been exposed through household contact.
  23. ↑ "Shionogi Enrolls the First Participant in Japan in its Global Phase 3 Trial of Ensitrelvir for the Prevention of Symptomatic SARS-CoV-2 Infection" (Press release). Osaka, Japan. 9 June 2023. Retrieved 28 October 2023.
  24. ↑ "The SCORPIO-PEP Study". SCORPIO-PEP. Shionogi Inc. Archived from the original on 11 May 2024. Retrieved 4 July 2024.
  25. ↑ Ernst D (8 November 2024). "Ensitrelvir Looks Promising for COVID-19 Postexposure Prophylaxis". MPR. Retrieved 25 January 2025.
  26. ↑ "Antiviral Prevents Symptomatic COVID-19 in Post-Exposure Prophylactic Study". ContagionLive. 29 October 2024. Retrieved 25 January 2025.
  27. ↑ Swift R (29 October 2024). "Japan's Shionogi says Phase 3 study showed COVID pill reduces transmission". Reuters. Retrieved 25 January 2025.
  28. ↑ Nobori H, Baba K, Kuroda T, Baba K, Matsumoto K, Yoshida S, et al. (April 2024). "Prophylactic effect of ensitrelvir in mice infected with SARS-CoV-2". Antiviral Research. 224: 105852. doi: 10.1016/j.antiviral.2024.105852 . PMID   38428748.
  29. ↑ Takazono T, Fujita S, Komeda T, Miyazawa S, Yoshida Y, Kitanishi Y, et al. (August 2024). "Real-World Effectiveness of Ensitrelvir in Reducing Severe Outcomes in Outpatients at High Risk for COVID-19". Infectious Diseases and Therapy. 13 (8): 1821–1833. doi: 10.1007/s40121-024-01010-4 . PMC   11266320 . PMID   38941067.
  30. ↑ Abe S, Wannigama DL, Suzuki Y, Akaneya D, Igarashi J, Suto M, et al. (1 December 2024). "Real world effectiveness of early ensitrelvir treatment in patients with SARS-CoV-2, a retrospective case series". New Microbes and New Infections. 62: 101522. doi:10.1016/j.nmni.2024.101522. ISSN   2052-2975. PMC   11567130 .
  31. ↑ Abene S (14 May 2024). "Ensitrelvir's Impact in COVID-19 Symptom Management and Relief". ContagionLive. Retrieved 8 September 2024.
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