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[5.3.2.0{2,6}.0{8,10}]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 became the first antipoxviral drug approved in the United States. [9] [10]

Contents

The drug works by blocking cellular transmission of the virus, thus preventing the disease. [11] It is an inhibitor of the orthopoxvirus VP37 envelope wrapping protein. [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. [6] Tecovirimat was first used for treatment in December 2018, after a laboratory-acquired vaccinia virus infection. [12]

Two million doses of tecovirimat are stockpiled in the US Strategic National Stockpile should an orthopoxvirus-based bioterror attack occur. [13] [14] The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication. [15]

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]

Mechanism of action

Tecovirimat inhibits the function of 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. [16]

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. [17]

Tecovirimat synthesis.svg

A Diels–Alder reaction of cycloheptatriene with maleic anhydride forms the main ring system [18] and then in the second step a reaction with 4-trifluormethylbenzhydrazide gives the cyclic imide of the drug. [17] [19]

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. [20]

Clinical trials

As of 2009, the results of clinical trials support its use against smallpox and other related orthopoxviruses. It shows potential for a variety of uses including preventive healthcare, as a post-exposure therapeutic, as a therapeutic, and an adjunct to vaccination. [21] [ failed verification ]

Tecovirimat can be taken by mouth and as of 2008, 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. [22] 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. On 13 July 2018, the FDA announced approval of tecovirimat for the treatment of smallpox. [23]

On 25 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. [24] [25]

Society and culture

In November 2021, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization under exceptional circumstances for the medicinal product tecovirimat SIGA, intended for the treatment of orthopoxvirus disease (smallpox, mpox, cowpox, and vaccinia complications) in adults and in children who weigh at least 13 kilograms (29 lb) [26] The applicant for this medicinal product is SIGA Technologies Netherlands B.V. [26] Tecovirimat was approved for medical use in the European Union in January 2022. [5] [27] [28]

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

As of August 2022, Tpoxx is available in the US only through the Strategic National Stockpile as a Centers for Disease Control and Prevention investigational new drug. [30] [31] Intravenous Tpoxx has no lower weight cap and can be used in infants under the investigational new drug protocol. [32]

Related Research Articles

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

The smallpox vaccine 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 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 of those infected will recover within a few weeks without treatment. The time from exposure to onset of symptoms ranges from five to twenty-one days and symptoms typically last from two to four weeks. Cases may be severe, especially in children, pregnant women or people with suppressed immune systems.

<span class="mw-page-title-main">Vaccinia</span> Strain of poxvirus

Vaccinia virus is a large, complex, enveloped virus belonging to the poxvirus family. It has a linear, double-stranded DNA genome approximately 190 kbp in length, which encodes approximately 250 genes. The dimensions of the virion are roughly 360 × 270 × 250 nm, with a mass of approximately 5–10 fg. The vaccinia virus is the source of the modern smallpox vaccine, which the World Health Organization (WHO) used to eradicate smallpox in a global vaccination campaign in 1958–1977. Although smallpox no longer exists in the wild, vaccinia virus is still studied widely by scientists as a tool for gene therapy and genetic engineering.

<span class="mw-page-title-main">Cidofovir</span> Antiviral drug

Cidofovir, brand name Vistide, is a topical or injectable antiviral medication primarily used as a treatment for cytomegalovirus (CMV) retinitis in people with AIDS.

<i>Poxviridae</i> Family of viruses

Poxviridae is a family of double-stranded DNA viruses. Vertebrates and arthropods serve as natural hosts. There are currently 83 species in this family, divided among 22 genera, which are divided into two subfamilies. Diseases associated with this family include smallpox.

Modified vaccinia Ankara (MVA) is an attenuated (weakened) strain of the vaccinia virus. It is being used as a vaccine against smallpox and mpox, having fewer side effects than smallpox vaccines derived from other poxviruses.

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">Smallpox</span> Eradicated viral disease

Smallpox was an infectious disease caused by variola virus, which belongs to the genus Orthopoxvirus. The last naturally occurring case was diagnosed in October 1977, and the World Health Organization (WHO) certified the global eradication of the disease in 1980, making smallpox the only human disease to have been eradicated to date.

<i>Monkeypox virus</i> 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. The monkeypox virus is a zoonotic virus belonging to the orthopoxvirus genus, making it closely related to the variola, cowpox, and vaccinia viruses. MPV is oval-shaped with a lipoprotein outer membrane. The genome is approximately 190 kb.

<span class="mw-page-title-main">2003 Midwest monkeypox outbreak</span> Outbreak of monkeypox in the United States

Beginning in May 2003, by July a total of 71 cases of human monkeypox were found in six Midwestern states including Wisconsin, Indiana (16), Illinois (12), Kansas (1), Missouri (2), and Ohio (1). The cause of the outbreak was traced to three species of African rodents imported from Ghana on April 9, 2003, into the United States by an exotic animal importer in Texas. These were shipped from Texas to an Illinois distributor, who housed them with prairie dogs, which then became infected.

Vaccinia immune globulin (VIG) is made from the pooled blood of individuals who have been inoculated with the smallpox vaccine. The antibodies these individuals developed in response to the smallpox vaccine are removed and purified. This results in VIG. It can be administered intravenously. It is used to treat individuals who have developed progressive vaccinia after smallpox vaccination.

<span class="mw-page-title-main">Brincidofovir</span> Antiviral drug

Brincidofovir, sold under the brand name Tembexa, is an antiviral drug used to treat smallpox. Brincidofovir is a prodrug of cidofovir. Conjugated to a lipid, the compound is designed to release cidofovir intracellularly, allowing for higher intracellular and lower plasma concentrations of cidofovir, effectively increasing its activity against dsDNA viruses, as well as oral bioavailability.

<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">Bavarian Nordic</span> Pharmaceutical company

Bavarian Nordic A/S is a fully integrated biotechnology company focused on the development, manufacturing and commercialization of vaccines. The company is headquartered in Hellerup, Denmark, with a manufacturing facility in Kvistgård, and an additional site in Hørsholm. The company has a research and development facility in Martinsried, Germany, and offices in Zug, Switzerland, and Morrisville, North Carolina. The company uses viral vectors in its research and development.

<span class="mw-page-title-main">Viral vector vaccine</span> Type of vaccine

A viral vector vaccine is a vaccine that uses a viral vector to deliver genetic material (DNA) that can be transcribed by the recipient's host cells as mRNA coding for a desired protein, or antigen, to elicit an immune response. As of April 2021, six viral vector vaccines, four COVID-19 vaccines and two Ebola vaccines, have been authorized for use in humans.

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

In May 2022, the World Health Organization (WHO) made an emergency announcement of the existence of a multi-country outbreak of mpox, a viral disease then commonly known as "monkeypox". The initial cluster of cases was found in the United Kingdom, where the first case was detected in London on 6 May 2022 in a patient with a recent travel history from Nigeria. On 16 May, the UK Health Security Agency (UKHSA) confirmed four new cases with no link to travel to a country where mpox is endemic. Subsequently, cases have been reported from many countries and regions. The outbreak marked the first time mpox had spread widely outside Central and West Africa. There is evidence that the disease had been circulating and evolving in human hosts over a number of years prior to the outbreak. The outbreak was of the Clade IIb variant of the virus.

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

The 2022–2023 mpox outbreak in the United States is part of the larger outbreak of human mpox caused by the West African clade of the monkeypox virus. The United States was the fourth country outside of the African countries with endemic mpox, to experience an outbreak in 2022. The first case was documented in Boston, Massachusetts, on May 17, 2022. As of August 22, mpox has spread to all 50 states in the United States, as well as Washington, D.C., and Puerto Rico. The United States has the highest number of mpox cases in the world. California has the highest number of mpox cases in the United States.

The 2022–2023 mpox outbreak in Belgium is part of the larger outbreak of human mpox caused by the West African clade of the monkeypox virus. Belgium was the fifth country, outside of the African countries with endemic mpox, to experience an outbreak in 2022. The first case was documented in Antwerp, Belgium, on 19 May 2022. As of 10 August, Belgium has 546 cases and 1 suspected case.

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.

<span class="mw-page-title-main">Mpox in the Democratic Republic of the Congo</span>

Mpox is endemic in western and central Africa, with the majority of cases occurring in the Democratic Republic of the Congo (DRC), where the disease is reportable. There, the more virulent Congo basin virus type has been affecting some of the world's poorest and socially excluded communities.

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. ↑ "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.
  10. ↑ "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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ Cunningham A (13 July 2018). "FDA approves the first smallpox treatment". Archived from the original on 12 July 2018. Retrieved 4 May 2018.
  15. ↑ 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.
  16. ↑ 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.
  17. 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
  18. ↑ 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 .
  19. ↑ 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.
  20. ↑ U.S. patent 8,124,643
  21. ↑ "SIGA Technologies". Archived from the original on 20 February 2012. Retrieved 18 September 2009.
  22. ↑ 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.
  23. ↑ 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.
  24. ↑ 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.
  25. ↑ "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.
  26. 1 2 "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.
  27. ↑ "Summary of Product Characteristics" (PDF). European Medicines Agency. Archived (PDF) from the original on 21 May 2022. Retrieved 24 May 2022.
  28. ↑ "Tecovirimat SIGA Product information". Union Register of medicinal products. Retrieved 3 March 2023.
  29. ↑ "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.
  30. ↑ "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.
  31. ↑ "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.
  32. ↑ "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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