Chemistry:Ensitrelvir

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Ensitrelvir, sold under the brand name Xocova is an antiviral medication used as a treatment for COVID-19.[1][2][3][4] It was developed by Shionogi in partnership with Hokkaido University and acts as an orally active 3C-like protease inhibitor.[5][6] It is taken by mouth.[7][8][9]

The most common adverse events include transient decreases in high-density lipoprotein and increased blood triglycerides.[7]

Medical uses

Ensitrelvir is indicated for the treatment of COVID-19.[7]

History

As of 2022, ensitrelvir had reached Phase III clinical trials.[10] 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.[11] In a study of 428 patients, viral load was reduced, but symptoms were not significantly reduced.[12]

In February 2022, the company sought emergency approval from regulators in Japan.[2][12]

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.[13]

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.[14]

Society and culture

Ensitrelvir was approved for emergency use in Japan in November 2022,[7][2][3] before gaining full approval in March 2024.[15] It was approved in Singapore in November 2023.[16]

In April 2023, ensitrelvir was given a "Fast Track" designation from the US Food and Drug Administration.[17]

Names

Ensitrelvir is the international nonproprietary name (INN).[18]

Research

Ensitrelvir has been investigated for use as potential post-exposure prophylaxis (PEP) for SARS-CoV-2 infection.[19][20] 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.[20][21][22][23] 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.[24][25][26]

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.[27]

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.[28] 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.[29]

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.[30]

References

  1. ↑ "Ensitrelvir as a potential treatment for COVID-19". Expert Opinion on Pharmacotherapy 23 (18): 1995–1998. December 2022. doi:10.1080/14656566.2022.2146493. PMID 36350029. 
  2. ↑ 2.0 2.1 2.2 "Japan Approves First Homegrown Covid-19 Antiviral Pill". 22 November 2022. https://www.wsj.com/articles/japan-approves-first-homegrown-covid-19-antiviral-pill-11669117019. 
  3. ↑ 3.0 3.1 "Shionogi's Covid antiviral lands first approval in Japan's new emergency approval pathway". 22 November 2022. https://endpts.com/shionogis-covid-antiviral-lands-first-approval-in-japans-new-emergency-approval-pathway/. 
  4. ↑ "Xocova: Powerful New Japanese Pill for Coronavirus Treatment.". BioPharma News. February 2022. https://biopharma.news/xocova-powerful-new-japanese-drug-for-coronavirus-treatment-3494/. 
  5. ↑ "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. May 2022. doi:10.1021/acs.jmedchem.2c00117. PMID 35352927. 
  6. ↑ "Shionogi presents positive Ph II/III results for COVID-19 antiviral S-217622". thepharmaletter.com. 31 January 2022. https://www.thepharmaletter.com/article/shionogi-presents-positive-ph-ii-iii-results-for-covid-19-antiviral-s-217622. 
  7. ↑ 7.0 7.1 7.2 7.3 "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.
  8. ↑ "Shionogi's new COVID pill appears to ease omicron symptoms.". Nikkei Asia. 21 December 2021. https://asia.nikkei.com/Spotlight/Coronavirus/Shionogi-s-new-COVID-pill-appears-to-ease-omicron-symptoms. 
  9. ↑ "Characterization and antiviral susceptibility of SARS-CoV-2 Omicron/BA.2". Nature 607 (7917): 119–127. May 2022. doi:10.1038/s41586-022-04856-1. PMID 35576972. Bibcode: 2022Natur.607..119U. 
  10. ↑ "S-217622, a 3CL Protease Inhibitor and Clinical Candidate for SARS-CoV-2". Journal of Medicinal Chemistry 65 (9): 6496–6498. May 2022. doi:10.1021/acs.jmedchem.2c00624. PMID 35507419. 
  11. ↑ "Japan to consider early approval for Shionogi COVID-19 pill.". Japan Times. 8 February 2022. https://www.japantimes.co.jp/news/2022/02/08/national/shionogi-covid-drug-early-approval/. 
  12. ↑ 12.0 12.1 "Japan's Shionogi seeks approval for COVID-19 pill". Reuters. 25 February 2022. https://www.reuters.com/business/healthcare-pharmaceuticals/japans-shionogi-seeks-approval-oral-covid-19-drug-2022-02-25/. 
  13. ↑ "Japan's Shionogi signs government supply pact for pill to fight COVID". Reuters. 25 March 2022. https://www.reuters.com/business/healthcare-pharmaceuticals/japans-shionogi-signs-govt-supply-pact-oral-covid-drug-2022-03-25/. 
  14. ↑ "New pill helps COVID smell and taste loss fade quickly" (in en). Nature. 2023-10-17. doi:10.1038/d41586-023-03244-7. PMID 37853192. https://www.nature.com/articles/d41586-023-03244-7. 
  15. ↑ "Japan health ministry approves Shionogi's COVID drug Xocova". 5 March 2024. https://www3.nhk.or.jp/nhkworld/en/news/20240305_19/. 
  16. ↑ "Shionogi reports data from Phase III portion of Covid-19 drug trial". 12 February 2024. https://www.clinicaltrialsarena.com/news/shionogi-covid-19-drug-trial-2/. 
  17. ↑ "When Will We Get New COVID-19 Drugs?". Time. 25 January 2024. https://time.com/6588624/covid-19-antiviral-treatments-us/. Retrieved 6 March 2024. 
  18. ↑ "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 88". WHO Drug Information 36 (3): 89. 2022. 
  19. ↑ "Ensitrelvir: A COVID-19 Antiviral That Remains Effective Against New Variants". 31 March 2023. https://www.contagionlive.com/view/ensitrelvir-a-covid-19-antiviral-that-remains-effective-against-new-variants. 
  20. ↑ 20.0 20.1 "Shionogi presses on with Xocova research following Japanese approval". 16 February 2023. https://www.thepharmaletter.com/article/shionogi-presses-on-with-xocova-research-following-japanese-approval. 
  21. ↑ "Studies Currently Enrolling". https://www.kumc.edu/school-of-medicine/campuses/wichita/research/center-for-clinical-research-wichita/clinical-trials/studies-currently-enrolling.html. "SCORPIO-PEP is a 28-day study to assess the prevention of COVID-19 infection in those who have been exposed through household contact." 
  22. ↑ "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.
  23. ↑ "The SCORPIO-PEP Study". Shionogi Inc.. https://scorpiopep.com/. 
  24. ↑ "Ensitrelvir Looks Promising for COVID-19 Postexposure Prophylaxis". 8 November 2024. https://www.empr.com/news/ensitrelvir-looks-promising-for-covid-19-postexposure-prophylaxis/. 
  25. ↑ "Antiviral Prevents Symptomatic COVID-19 in Post-Exposure Prophylactic Study". 29 October 2024. https://www.contagionlive.com/view/antiviral-prevents-symptomatic-covid-19-in-post-exposure-prophylactic-study. 
  26. ↑ "Japan's Shionogi says Phase 3 study showed COVID pill reduces transmission". 29 October 2024. https://www.reuters.com/business/healthcare-pharmaceuticals/japans-shionogi-says-phase-3-study-showed-covid-pill-reduces-transmission-2024-10-29/. 
  27. ↑ "Prophylactic effect of ensitrelvir in mice infected with SARS-CoV-2". Antiviral Research 224. April 2024. doi:10.1016/j.antiviral.2024.105852. PMID 38428748. 
  28. ↑ "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. August 2024. doi:10.1007/s40121-024-01010-4. PMID 38941067. 
  29. ↑ "Real world effectiveness of early ensitrelvir treatment in patients with SARS-CoV-2, a retrospective case series". New Microbes and New Infections 62. 2024-12-01. doi:10.1016/j.nmni.2024.101522. ISSN 2052-2975. PMID 39552926. 
  30. ↑ "Ensitrelvir's Impact in COVID-19 Symptom Management and Relief". 14 May 2024. https://www.contagionlive.com/view/ensitrelvir-s-impact-in-covid-19-symptom-management-and-relief. 



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