Tecovirimat

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Tecovirimat
Tecovirimat.svg
Clinical data
Trade names Tpoxx
Other namesST-246
AHFS/Drugs.com Monograph
License data
Routes of
administration 		By mouth, intravenous
ATC code
Legal status
Legal status
Identifiers
  • N-{3,5-Dioxo-4-azatetracyclo[5.3.2.02,6.08,10]dodec-11-en-4-yl}-4-(trifluoromethyl)benzamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C19H15F3N2O3
Molar mass 376.335 g·mol−1
3D model (JSmol)
  • FC(F)(F)c1ccc(cc1)C(=O)NN1C(=O)C2C(C3C=CC2C2CC32)C1=O
  • InChI=1S/C19H15F3N2O3/c20-19(21,22)9-3-1-8(2-4-9)16(25)23-24-17(26)14-10-5-6-11(13-7-12(10)13)15(14)18(24)27/h1-6,10-15H,7H2,(H,23,25) Yes check.svgY
  • Key:CSKDFZIMJXRJGH-UHFFFAOYSA-N Yes check.svgY

Tecovirimat, sold under the brand name Tpoxx among others, [6] is an antiviral medication with activity against orthopoxviruses such as smallpox and mpox. [4] [7] [8] In 2018 it was the first antipoxviral drug approved in the United States.

Contents

The drug works by blocking cellular transmission of orthopoxviruses, thus preventing disease. [9]

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. [6] Tecovirimat was first used for treatment in December 2018, after a laboratory-acquired vaccinia virus infection. [10]

As of 2014 two million doses of tecovirimat were stockpiled in the US Strategic National Stockpile should an orthopoxvirus-based bioterror attack occur. [11] [12] The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication. [13]

Medical uses

In the United States, tecovirimat is indicated for the treatment of human smallpox disease. [4]

In the European Union it is indicated for the treatment of smallpox, mpox, and cowpox. [5] Tecovirimat can be taken by mouth and should be taken with a fatty meal. [14]

Mechanism of action

Tecovirimat inhibits the function of orthopoxvirus VP37 envelope wrapping protein, [4] 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. [15]

Antimicrobial resistance to tecovirimat was described in vitro in cowpox virus during treatment already in 2005, prior to licensure. [14] 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. [14]

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. [16]

Tecovirimat synthesis.svg

A Diels–Alder reaction of cycloheptatriene with maleic anhydride forms the main ring system [17] and then in the second step a reaction with 4-trifluormethylbenzhydrazide gives the cyclic imide of the drug. [16] [18]

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.[ citation needed ] It is owned and manufactured by SIGA Technologies.[ citation needed ] SIGA and Viropharma were issued a patent for tecovirimat in 2012. [19]

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. [20] [ failed verification ]

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. [21] 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. [22] the first antipoxviral drug approved in the United States. [23] [24] 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. [25] [26]

Society and culture

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 13 kilograms (29 lb) [27] Tecovirimat was approved for medical use in the European Union in January 2022. [5] [28] [29]

In December 2021, Health Canada approved oral tecovirimat for the treatment of smallpox in people weighing at least 13 kilograms (29 lb). [1] [30]

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. [31] [32] As of 2022, intravenous Tpoxx had no lower weight cap and can be used in infants under the investigational new drug protocol. [33]

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. [14]

Related Research Articles

<span class="mw-page-title-main">Smallpox vaccine</span> Vaccine against Variola virus

The smallpox vaccine is used to prevent smallpox infection caused by the variola virus. It is the first vaccine to have been developed against a contagious disease. In 1796, British physician Edward Jenner demonstrated that an infection with the relatively mild cowpox virus conferred immunity against the deadly smallpox virus. Cowpox served as a natural vaccine until the modern smallpox vaccine emerged in the 20th century. From 1958 to 1977, the World Health Organization (WHO) conducted a global vaccination campaign that eradicated smallpox, making it the only human disease to be eradicated. Although routine smallpox vaccination is no longer performed on the general public, the vaccine is still being produced for research, and to guard against bioterrorism, biological warfare, and mpox.

<span class="mw-page-title-main">Mpox</span> Viral disease of humans and animals

Mpox is an infectious viral disease that can occur in humans and other animals. Symptoms include a rash that forms blisters and then crusts over, fever, and swollen lymph nodes. The illness is usually mild, and most infected individuals recover within a few weeks without treatment. The time from exposure to the onset of symptoms ranges from three to seventeen days, and symptoms typically last from two to four weeks. However, cases may be severe, especially in children, pregnant women, or people with suppressed immune systems.

Orthopoxvirus is a genus of viruses in the family Poxviridae and subfamily Chordopoxvirinae. Vertebrates, including mammals and humans, and arthropods serve as natural hosts. There are 12 species in this genus. Diseases associated with this genus include smallpox, cowpox, horsepox, camelpox, and mpox. The most widely known member of the genus is Variola virus, which causes smallpox. It was eradicated globally by 1977, through the use of Vaccinia virus as a vaccine. The most recently described species is the Alaskapox virus, first isolated in 2015.

<span class="mw-page-title-main">Monkeypox virus</span> Species of double-stranded DNA virus

The monkeypox virus is a species of double-stranded DNA virus that causes mpox disease in humans and other mammals. It is a zoonotic virus belonging to the Orthopoxvirus genus, making it closely related to the variola, cowpox, and vaccinia viruses. MPV is oval, with a lipoprotein outer membrane. The genome is approximately 190 kb. Smallpox and monkeypox viruses are both orthopoxviruses, and the smallpox vaccine is effective against mpox if given within 3–5 years before the disease is contracted. Symptoms of mpox in humans include a rash that forms blisters and then crusts over, fever, and swollen lymph nodes. The virus is transmissible between animals and humans by direct contact to the lesions or bodily fluids. The virus was given the name monkeypox virus after being isolated from monkeys, but most of the carriers of this virus are smaller mammals.

<span class="mw-page-title-main">SIGA Technologies</span> American pharmaceutical

SIGA Technologies, Inc. is an American pharmaceutical company founded in 1995, based in New York City, which develops and sells pharmaceutical solutions for the antiviral treatment of smallpox, monkeypox, cowpox, and vaccinia complications.

<span class="mw-page-title-main">2022–2023 mpox outbreak in Canada</span> Ongoing viral outbreak

The 2022–2023 mpox outbreak in Canada is a part of the outbreak of human mpox caused by the West African clade of the monkeypox virus. The outbreak started in Canada on May 19, 2022, with the country since then becoming one of the most affected in the Americas.

The 2022–2023 mpox outbreak in Portugal is part of the larger outbreak of human mpox caused by the West African clade of the monkeypox virus. Portugal was the third country, outside of the African countries with endemic mpox, to experience an outbreak in 2022.

The 2022–2023 mpox outbreak in Italy is part of the larger outbreak of human mpox caused by the West African clade of the monkeypox virus. Italy was the sixth country, outside of the African countries with endemic mpox, to experience an outbreak in 2022. The first case was documented in Rome, Italy, on May 19, 2022. As of August 5th, Italy has 505 cases.

The 2022 – 2023 mpox outbreak in France is part of the larger outbreak of human mpox caused by the West African clade of the monkeypox virus. France had its first case on 20 May 2022.

The 2022–2023 mpox outbreak in Israel is a part of the ongoing outbreak of human mpox caused by the West African clade of the monkeypox virus. The outbreak was first reported in Israel on 20 May 2022 when the Health Ministry announced a suspected case which was confirmed on 21 May 2022. One month later, on 21 June, the first locally transmitted case was reported.

The 2022–2023 mpox outbreak in Switzerland is a part of the outbreak of human mpox caused by the West African clade of the monkeypox virus. The outbreak started in Switzerland on 19 May 2022, with the country since then becoming one of the most affected in Europe.

The 2022–2023 mpox outbreak in Austria is part of the larger outbreak of human mpox caused by the West African clade of the monkeypox virus. Austria is the fifteenth country outside of Africa to experience an endemic mpox outbreak. The first case was reported in Vienna, Austria, on 22 May 2022. As of 2 December, Austria has confirmed a total of 327 cases.

<span class="mw-page-title-main">2022–2023 mpox outbreak in Mexico</span> Ongoing viral outbreak

The 2022–2023 mpox outbreak in Mexico is part of the larger outbreak of human mpox caused by the West African clade of the monkeypox virus. Mexico is the twenty-fourth country outside of Africa to experience an endemic mpox outbreak. The first case was reported in Mexico City, Mexico, on May 28, 2022. As of December 8th 2022, Mexico had confirmed a total of 3455 cases in all 32 states and 4 deaths.

The 2022–2023 mpox outbreak in the Netherlands is an ongoing global outbreak which has also spread in the Netherlands. The RIVM declared the disease an A-disease which makes it mandatory to report suspected cases to the GGD. The first human case of mpox in the Netherlands has been identified at the 21 May 2022. The outbreak does have a noticeable impact at the society, especially with people spreading misinformation related to the virus. The ongoing COVID-19 pandemic in the Netherlands has increased the fear among the community for a new pandemic like mpox.

The 2022–2023 mpox outbreak in South Africa is a part of the larger outbreak of human mpox caused by the West African clade of the monkeypox virus. South Africa was the forty-seventh country, outside of the African countries with endemic mpox, to experience an outbreak in 2022. The first case of mpox in South Africa was on June 23, 2022.

<span class="mw-page-title-main">2022–2023 mpox outbreak in Japan</span> Outbreak of mpox in Japan

The 2022–2023 mpox outbreak in Japan is a part of the larger outbreak of human mpox caused by the West African clade of the monkeypox virus. According to the Ministry of Health, Japan's first mpox case was reported in Tokyo on 25 July 2022.

<span class="mw-page-title-main">2022–2023 mpox outbreak in Chile</span> Ongoing viral outbreak

The 2022–2023 mpox outbreak in Chile is a part of the outbreak of human mpox caused by the West African clade of the monkeypox virus. The outbreak reached Chile on 17 June 2022.

The 2022–2023 mpox outbreak in Singapore is a part of the global outbreak of human mpox caused by the West African clade of the monkeypox virus. According to the Ministry of Health (MOH), Singapore's first imported mpox case was reported on 20 June 2022. It was the first ever confirmed case in Southeast Asia.

The 2022–2023 mpox outbreak in Ghana is a part of the larger outbreak of human mpox caused by the West African clade of the monkeypox virus. As opposed to its West African neighbours, Ghana had no endemic presence of mpox, only experiencing it during the 2022 outbreak. The first 5 cases of mpox in Ghana was detected on June 8, 2022.

The 2022-2023 mpox outbreak in the Republic of Ireland is part of the larger ongoing global outbreak of human mpox caused by Clade II of the monkeypox virus. The first case in the Republic was confirmed on 27 May 2022.

References

  1. 1 2 "Notice: Multiple Additions to the Prescription Drug List (PDL) [2022-01-24]". Health Canada. 24 January 2022. Archived from the original on 29 May 2022. Retrieved 28 May 2022.
  2. ↑ "New Medicines Approved in 2018". Health Canada. 15 January 2020. Archived from the original on 29 May 2022. Retrieved 28 May 2022.
  3. ↑ "Summary Basis of Decision (SBD) for Tpoxx". Health Canada. 23 October 2014. Archived from the original on 29 May 2022. Retrieved 29 May 2022.
  4. 1 2 3 4 "Tpoxx- tecovirimat monohydrate capsule". DailyMed. 2 December 2021. Archived from the original on 23 April 2022. Retrieved 23 April 2022.
  5. 1 2 3 "Tecovirimat SIGA EPAR". European Medicines Agency. 10 November 2021. Archived from the original on 16 May 2022. Retrieved 23 April 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  6. 1 2 McNeil Jr DG (13 July 2018). "Drug to Treat Smallpox Approved by F.D.A., a Move Against Bioterrorism". The New York Times . Archived from the original on 28 March 2019. Retrieved 16 July 2018.
  7. ↑ Nakoune E, Olliaro P (May 2022). "Waking up to monkeypox". BMJ. 377: o1321. doi: 10.1136/bmj.o1321 . PMID   35613732. S2CID   249047112.
  8. ↑ Adler H, Gould S, Hine P, Snell LB, Wong W, Houlihan CF, et al. (May 2022). "Clinical features and management of human monkeypox: a retrospective observational study in the UK". The Lancet. Infectious Diseases. 22 (8): 1153–1162. doi:10.1016/S1473-3099(22)00228-6. PMC   9300470 . PMID   35623380. S2CID   249057804.
  9. ↑ Grosenbach DW, Honeychurch K, Rose EA, Chinsangaram J, Frimm A, Maiti B, et al. (July 2018). "Oral Tecovirimat for the Treatment of Smallpox". The New England Journal of Medicine. 379 (1): 44–53. doi:10.1056/NEJMoa1705688. PMC   6086581 . PMID   29972742.
  10. ↑ Whitehouse ER, Rao AK, Yu YC, Yu PA, Griffin M, Gorman S, et al. (October 2019). "Novel Treatment of a Vaccinia Virus Infection from an Occupational Needlestick - San Diego, California, 2019" (PDF). MMWR. Morbidity and Mortality Weekly Report. 68 (42): 943–946. doi:10.15585/mmwr.mm6842a2. PMC   6812835 . PMID   31647789. Archived (PDF) from the original on 2 August 2022. Retrieved 2 August 2022.
  11. ↑ Damon IK, Damaso CR, McFadden G (May 2014). "Are we there yet? The smallpox research agenda using variola virus". PLOS Pathogens. 10 (5): e1004108. doi: 10.1371/journal.ppat.1004108 . PMC   4006926 . PMID   24789223.
  12. ↑ Cunningham A (13 July 2018). "FDA approves the first smallpox treatment". Archived from the original on 12 July 2018. Retrieved 4 May 2018.
  13. ↑ New Drug Therapy Approvals 2018 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2019. Archived from the original on 17 September 2020. Retrieved 16 September 2020.
  14. 1 2 3 4 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. 73 (40): 903–905. doi:10.15585/mmwr.mm7340a3. ISSN   0149-2195. PMC   11466377 .
  15. ↑ Yang G, Pevear DC, Davies MH, Collett MS, Bailey T, Rippen S, et al. (October 2005). "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. doi:10.1128/JVI.79.20.13139-13149.2005. PMC   1235851 . PMID   16189015.
  16. 1 2 AUpatent 2004249250,Bailey, Thomas R.; Jordan, Robert& Rippin, Susan R.,"Compounds, compositions and methods for treatment and prevention of orthopoxvirus infections and associated diseases",published 2004-12-29, assigned to SIGA Pharmaceuticals Inc
  17. ↑ Ishitobi H, Tanida H, Tori K, Tsuji T (1971). "Re-examination of the Cycloaddition of Cycloheptatriene with Maleic Anhydride". Bulletin of the Chemical Society of Japan. 44 (11): 2993–3000. doi: 10.1246/bcsj.44.2993 .
  18. ↑ Hughes DL (2019). "Review of the Patent Literature: Synthesis and Final Forms of Antiviral Drugs Tecovirimat and Baloxavir Marboxil". Organic Process Research & Development. 23 (7): 1298–1307. doi:10.1021/acs.oprd.9b00144. S2CID   197172102.
  19. ↑ U.S. patent 8,124,643
  20. ↑ "SIGA Technologies". Archived from the original on 20 February 2012. Retrieved 18 September 2009.
  21. ↑ Jordan R, Tien D, Bolken TC, Jones KF, Tyavanagimatt SR, Strasser J, et al. (May 2008). "Single-dose safety and pharmacokinetics of ST-246, a novel orthopoxvirus egress inhibitor". Antimicrobial Agents and Chemotherapy. 52 (5): 1721–1727. doi:10.1128/AAC.01303-07. PMC   2346641 . PMID   18316519.
  22. ↑ Office of the Commissioner (24 March 2020). "Press Announcements - FDA approves the first drug with an indication for treatment of smallpox". Food and Drug Administration (FDA). Archived from the original on 23 April 2019. Retrieved 14 July 2018.
  23. ↑ "FDA approves the first drug with an indication for treatment of smallpox". U.S. Food and Drug Administration (FDA) (Press release). 13 July 2018. Archived from the original on 23 April 2019. Retrieved 1 August 2018.
  24. ↑ "U.S. Food and Drug Administration Approves Siga Technologies' Tpoxx (tecovirimat) for the Treatment of Smallpox". SIGA (Press release). Archived from the original on 21 September 2018. Retrieved 14 July 2018.
  25. ↑ National Institute of Allergy and Infectious Diseases (NIAID) (12 September 2022). "A Randomized, Placebo-Controlled, Double-Blinded Trial of the Safety and Efficacy of Tecovirimat for the Treatment of Human Monkeypox Virus Disease". SIGA Technologist. Archived from the original on 20 September 2022. Retrieved 16 September 2022.
  26. ↑ "Trial Launching to Study Tecovirimat as Monkeypox Treatment". Contagion Live. 16 September 2022. Archived from the original on 16 September 2022. Retrieved 16 September 2022.
  27. ↑ "Tecovirimat SIGA: Pending EC decision". European Medicines Agency. 11 November 2021. Archived from the original on 13 November 2021. Retrieved 13 November 2021. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  28. ↑ "Summary of Product Characteristics" (PDF). European Medicines Agency. Archived (PDF) from the original on 21 May 2022. Retrieved 24 May 2022.
  29. ↑ "Tecovirimat SIGA Product information". Union Register of medicinal products. Retrieved 3 March 2023.
  30. ↑ "SIGA Announces Health Canada Regulatory Approval of Oral Tpoxx" (Press release). Siga Technologies. 1 December 2021. Archived from the original on 24 May 2022. Retrieved 24 May 2022.
  31. ↑ "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. Archived from the original on 31 July 2022. Retrieved 1 August 2022.
  32. ↑ "Steps for Clinicians to Order Medication to Treat Monkeypox". Coca Now. 19 July 2022. Archived from the original on 2 August 2022. Retrieved 24 July 2022.
  33. ↑ "Monkeypox Outbreak: Updates on the Epidemiology, Testing, Treatment, and Vaccination" (PDF). U.S. Centers for Disease Control and Prevention . Archived (PDF) from the original on 2 August 2022. Retrieved 27 July 2022.
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