Tecovirimat Explained

Tecovirimat, sold under the brand name Tpoxx among others,[1] is an antiviral medication with activity against orthopoxviruses such as smallpox and mpox.[2] [3] In 2018 it was the first antipoxviral drug approved in the United States.

The drug works by blocking cellular transmission of orthopoxviruses, thus preventing disease.[4]

Tecovirimat has been effective in laboratory testing; it has been shown to protect animals from mpox and rabbitpox and causes no serious side effects in humans. Tecovirimat was first used for treatment in December 2018, after a laboratory-acquired vaccinia virus infection.[5]

As of 2014 two million doses of tecovirimat were stockpiled in the US Strategic National Stockpile should an orthopoxvirus-based bioterror attack occur.[6] [7] The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.[8]

Medical uses

In the United States, tecovirimat is indicated for the treatment of human smallpox disease.

In the European Union it is indicated for the treatment of smallpox, mpox, and cowpox.Tecovirimat can be taken by mouth and should be taken with a fatty meal.

Mechanism of action

Tecovirimat inhibits the function of orthopoxvirus VP37 envelope wrapping protein, a major envelope protein required for the production of extracellular virus. The drug prevents the virus from leaving an infected cell, hindering the spread of the virus within the body.[9]

Antimicrobial resistance to tecovirimat was described in vitro in cowpox virus during treatment already in 2005, prior to licensure.[10] Since the global 2022–2023 mpox outbreak, resistance has been described with long treatment courses among severely immunocompromised persons, but also in people without prior treatment, suggesting human-to-human transmission.

Chemistry

The first synthesis of tecovirimat was published in a patent filed by scientists at SIGA Technologies in 2004. It is made in two steps from cycloheptatriene.[11]

A Diels–Alder reaction of cycloheptatriene with maleic anhydride forms the main ring system[12] and then in the second step a reaction with 4-trifluormethylbenzhydrazide gives the cyclic imide of the drug.[11] [13]

History

Originally researched by the National Institute of Allergy and Infectious Diseases, the drug was owned by Viropharma and discovered in collaboration with scientists at the United States Army Medical Research Institute of Infectious Diseases. It is owned and manufactured by SIGA Technologies. SIGA and Viropharma were issued a patent for tecovirimat in 2012.

Clinical trials

As of 2009, the results of clinical trials supported its use against smallpox and other related orthopoxviruses. It showed potential for a variety of uses including preventive healthcare, as a post-exposure therapeutic, as a therapeutic, and an adjunct to vaccination.[14]

As of 2008, it was permitted for phase II trials by the U.S. Food and Drug Administration (FDA). In phase I trials, tecovirimat was generally well tolerated with no serious adverse events.[15] Due to its importance for biodefense, the FDA designated tecovirimat for fast-track status, creating a path for expedited FDA review and eventual regulatory approval. In July 2018, the FDA approved tecovirimat for the treatment of smallpox.[16] the first antipoxviral drug approved in the United States.[17] [18] In August 2022, the AIDS Clinical Trials Group (ACTG) began a randomized, placebo-controlled, double-blinded trial on the safety and efficacy of tecovirimat for mpox, known as STOMP (Study of Tecovirimat for Human mpox Virus), aiming to enroll at least 500 participants with acute mpox infection.[19] [20]

Society and culture

Legal status

In November 2021, the Committee for Medicinal Products for Human Use of the European Medicines Agency recommended to grant SIGA Technologies Netherlands B.V a marketing authorization under exceptional circumstances for tecovirimat, intended to treat orthopoxvirus disease (smallpox, mpox, cowpox, and vaccinia complications) in adults and in children who weigh at least 13kg (29lb)[21] Tecovirimat was approved for medical use in the European Union in January 2022.[22] [23] [24]

In December 2021, Health Canada approved oral tecovirimat for the treatment of smallpox in people weighing at least 13kg (29lb).[25]

As of August 2022, Tpoxx was available in the US only through the Strategic National Stockpile as a Centers for Disease Control and Prevention investigational new drug.[26] [27] As of 2022, intravenous Tpoxx had no lower weight cap and can be used in infants under the investigational new drug protocol.[28]

As of 2024, tecovirimat use in the US outside of a clinical trial should adhere to the CDC Investigational New Drug protocol in order to prevent mutations and to include surveillance to prevent spread of resistant virus.

External links

Notes and References

  1. News: McNeil Jr DG . Drug to Treat Smallpox Approved by F.D.A., a Move Against Bioterrorism . . 13 July 2018 . 16 July 2018 . 28 March 2019 . https://web.archive.org/web/20190328145843/https://www.nytimes.com/2018/07/13/health/smallpox-drug-fda-bioterrorism.html . live .
  2. Nakoune E, Olliaro P . Waking up to monkeypox . BMJ . 377 . o1321 . May 2022 . 35613732 . 10.1136/bmj.o1321 . 249047112 . free .
  3. Adler H, Gould S, Hine P, Snell LB, Wong W, Houlihan CF, Osborne JC, Rampling T, Beadsworth MB, Duncan CJ, Dunning J, Fletcher TE, Hunter ER, Jacobs M, Khoo SH, Newsholme W, Porter D, Porter RJ, Ratcliffe L, Schmid ML, Semple MG, Tunbridge AJ, Wingfield T, Price NM . 6 . Clinical features and management of human monkeypox: a retrospective observational study in the UK . The Lancet. Infectious Diseases . May 2022 . 22 . 8 . 1153–1162 . 35623380 . 10.1016/S1473-3099(22)00228-6 . 9300470 . 249057804 .
  4. Grosenbach DW, Honeychurch K, Rose EA, Chinsangaram J, Frimm A, Maiti B, Lovejoy C, Meara I, Long P, Hruby DE . 6 . Oral Tecovirimat for the Treatment of Smallpox . The New England Journal of Medicine . 379 . 1 . 44–53 . July 2018 . 29972742 . 6086581 . 10.1056/NEJMoa1705688 .
  5. Whitehouse ER, Rao AK, Yu YC, Yu PA, Griffin M, Gorman S, Angel KA, McDonald EC, Manlutac AL, de Perio MA, McCollum AM, Davidson W, Wilkins K, Ortega E, Satheshkumar PS, Townsend MB, Isakari M, Petersen BW . 6 . Novel Treatment of a Vaccinia Virus Infection from an Occupational Needlestick - San Diego, California, 2019 . MMWR. Morbidity and Mortality Weekly Report . 68 . 42 . 943–946 . October 2019 . 31647789 . 6812835 . 10.15585/mmwr.mm6842a2 . 2 August 2022 . 2 August 2022 . https://web.archive.org/web/20220802054811/https://www.cdc.gov/mmwr/volumes/68/wr/pdfs/mm6842a2-H.pdf . live .
  6. Damon IK, Damaso CR, McFadden G . Are we there yet? The smallpox research agenda using variola virus . PLOS Pathogens . 10 . 5 . e1004108 . May 2014 . 24789223 . 4006926 . 10.1371/journal.ppat.1004108 . free .
  7. Web site: FDA approves the first smallpox treatment. Cunningham A . 13 July 2018. 4 May 2018. 12 July 2018. https://web.archive.org/web/20180712230149/https://www.sciencenews.org/article/first-smallpox-treatment-one-step-closer-fda-approval. live .
  8. New Drug Therapy Approvals 2018 . U.S. Food and Drug Administration (FDA) . January 2019 . PDF . 16 September 2020 . 17 September 2020 . https://web.archive.org/web/20200917055627/https://www.fda.gov/media/120357/download . live .
  9. Yang G, Pevear DC, Davies MH, Collett MS, Bailey T, Rippen S, Barone L, Burns C, Rhodes G, Tohan S, Huggins JW, Baker RO, Buller RL, Touchette E, Waller K, Schriewer J, Neyts J, DeClercq E, Jones K, Hruby D, Jordan R . 6 . An orally bioavailable antipoxvirus compound (ST-246) inhibits extracellular virus formation and protects mice from lethal orthopoxvirus Challenge . Journal of Virology . 79 . 20 . 13139–13149 . October 2005 . 16189015 . 1235851 . 10.1128/JVI.79.20.13139-13149.2005 .
  10. Gigante . Crystal M. . 2024 . Notes from the Field: Mpox Cluster Caused by Tecovirimat-Resistant Monkeypox Virus — Five States, October 2023–February 2024 . MMWR. Morbidity and Mortality Weekly Report . en-us . 73 . 40 . 903–905 . 10.15585/mmwr.mm7340a3 . 0149-2195. 11466377 .
  11. AU . 2004249250. patent . 2004-12-29 . 2004-06-18 . 2003-06-20 . Bailey, Thomas R. . Jordan, Robert . Rippin, Susan R. . Compounds, compositions and methods for treatment and prevention of orthopoxvirus infections and associated diseases . SIGA Pharmaceuticals Inc .
  12. 10.1246/bcsj.44.2993 . free . Re-examination of the Cycloaddition of Cycloheptatriene with Maleic Anhydride . 1971 . Ishitobi H, Tanida H, Tori K, Tsuji T . Bulletin of the Chemical Society of Japan . 44 . 11 . 2993–3000 .
  13. 10.1021/acs.oprd.9b00144 . Review of the Patent Literature: Synthesis and Final Forms of Antiviral Drugs Tecovirimat and Baloxavir Marboxil . 2019 . Hughes DL . Organic Process Research & Development . 23 . 7 . 1298–1307 . 197172102 .
  14. Web site: SIGA Technologies . 18 September 2009 . 20 February 2012 . https://web.archive.org/web/20120220165844/http://www.siga.com/index.php?ID=9 . live .
  15. Jordan R, Tien D, Bolken TC, Jones KF, Tyavanagimatt SR, Strasser J, Frimm A, Corrado ML, Strome PG, Hruby DE . 6 . Single-dose safety and pharmacokinetics of ST-246, a novel orthopoxvirus egress inhibitor . Antimicrobial Agents and Chemotherapy . 52 . 5 . 1721–1727 . May 2008 . 18316519 . 2346641 . 10.1128/AAC.01303-07 .
  16. Web site: Press Announcements - FDA approves the first drug with an indication for treatment of smallpox. Office of the Commissioner . Food and Drug Administration (FDA). 24 March 2020. 14 July 2018. 23 April 2019. https://web.archive.org/web/20190423072008/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm613496.htm. live.
  17. FDA approves the first drug with an indication for treatment of smallpox . U.S. Food and Drug Administration (FDA) . 1 August 2018 . 13 July 2018 . 23 April 2019 . https://web.archive.org/web/20190423072008/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm613496.htm . live .
  18. U.S. Food and Drug Administration Approves Siga Technologies' Tpoxx (tecovirimat) for the Treatment of Smallpox. SIGA. 14 July 2018. 21 September 2018. https://web.archive.org/web/20180921045623/http://investor.siga.com/news-releases/news-release-details/us-food-and-drug-administration-approves-siga-technologies. live.
  19. Web site: National Institute of Allergy and Infectious Diseases (NIAID) . 12 September 2022 . SIGA Technologist . A Randomized, Placebo-Controlled, Double-Blinded Trial of the Safety and Efficacy of Tecovirimat for the Treatment of Human Monkeypox Virus Disease . 16 September 2022 . 20 September 2022 . https://web.archive.org/web/20220920163558/https://clinicaltrials.gov/ct2/show/NCT05534984 . live .
  20. Web site: Trial Launching to Study Tecovirimat as Monkeypox Treatment . 16 September 2022 . Contagion Live . 16 September 2022 . en . 16 September 2022 . https://web.archive.org/web/20220916154518/https://www.contagionlive.com/view/trial-launching-to-study-tecovirimat-as-monkeypox-treatment . live .
  21. Web site: Tecovirimat SIGA: Pending EC decision . European Medicines Agency . 11 November 2021 . 13 November 2021 . 13 November 2021 . https://web.archive.org/web/20211113051720/https://www.ema.europa.eu/en/medicines/human/summaries-opinion/tecovirimat-siga . live . Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  22. Web site: Tecovirimat SIGA EPAR . European Medicines Agency . 10 November 2021 . 23 April 2022 . 16 May 2022 . https://web.archive.org/web/20220516151355/https://www.ema.europa.eu/en/medicines/human/EPAR/tecovirimat-siga . live . Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  23. Web site: Summary of Product Characteristics . European Medicines Agency . 24 May 2022 . 21 May 2022 . https://web.archive.org/web/20220521134209/https://www.ema.europa.eu/en/documents/product-information/tecovirimat-siga-epar-product-information_en.pdf . live .
  24. Web site: Tecovirimat SIGA Product information . Union Register of medicinal products . 3 March 2023.
  25. . SIGA Announces Health Canada Regulatory Approval of Oral Tpoxx . Siga Technologies . 1 December 2021 . 24 May 2022 . 24 May 2022 . https://web.archive.org/web/20220524072038/https://investor.siga.com/news-releases/news-release-details/siga-announces-health-canada-regulatory-approval-oral-tpoxxr . live .
  26. Web site: Information for Healthcare Providers on Obtaining and Using TPOXX (Tecovirimat) for Treatment of Monkeypox . U.S. Centers for Disease Control and Prevention (CDC) . 22 July 2022 . 1 August 2022 . 31 July 2022 . https://web.archive.org/web/20220731125437/https://www.cdc.gov/poxvirus/monkeypox/clinicians/obtaining-tecovirimat.html . live .
  27. 19 July 2022 . Steps for Clinicians to Order Medication to Treat Monkeypox . Coca Now . 24 July 2022 . 2 August 2022 . https://web.archive.org/web/20220802054814/https://emergency.cdc.gov/newsletters/coca/071922.htm . live .
  28. Web site: Monkeypox Outbreak: Updates on the Epidemiology, Testing, Treatment, and Vaccination . U.S. Centers for Disease Control and Prevention. 27 July 2022 . 2 August 2022 . https://web.archive.org/web/20220802054812/https://emergency.cdc.gov/coca/ppt/2022/072622_slides.pdf . live .

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