Fexinidazole

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Fexinidazole
Fexinidazole.svg
Clinical data
Other names
  • Fexinidazole Winthrop
  • HOE 239
License data
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Identifiers
  • 1-Methyl-2-{[4-(methylsulfanyl)phenoxy]methyl}-5-nitro-1H-imidazole
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.207.619 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C12H13N3O3S
Molar mass 279.31 g·mol−1
3D model (JSmol)
  • [O-] [N+](=O)c1cnc(n1C)COc2ccc(SC)cc2
  • InChI=1S/C12H13N3O3S/c1-14-11(13-7-12(14)15(16)17)8-18-9-3-5-10(19-2)6-4-9/h3-7H,8H2,1-2H3
  • Key:MIWWSGDADVMLTG-UHFFFAOYSA-N

Fexinidazole is a medication used to treat African trypanosomiasis (sleeping sickness) caused by Trypanosoma brucei gambiense . [3] It is effective against both first and second stage disease. [3] Also a potential new treatment for Chagas disease, a neglected tropical disease that affects millions of people worldwide. [4] It is taken by mouth. [5]

Contents

Common side effects include nausea, vomiting, headache, and trouble sleeping. [6] Other side effects may include QT prolongation, psychosis, and low white blood cells. [7] It is unclear if use during pregnancy or breast feeding is safe. [7] Fexinidazole is in the antiparasitic and the nitroimidazole family of medications. [5] It is believed to work by turning on certain enzymes within the parasites that result in their death. [6]

Fexinidazole was first described in 1978. [8] It was given a positive opinion by the European Medicines Agency in 2018. [6] It is on the World Health Organization's List of Essential Medicines. [9] [10] Development for sleeping sickness was funded by the Drugs for Neglected Diseases initiative in collaboration with Sanofi. [11] Fexinidazole was approved for medical use in the United States in July 2021. [1]

Medical use

Sleeping sickness

A trial in Africa found fexinidazole to be 91% effective at treating sleeping sickness. [6] [12] Though less effective than nifurtimox with eflornithine in severe disease, fexinidazole has the benefit that it can be taken by mouth. [6]

Fexinidazole is the first drug candidate for the treatment of advanced-stage sleeping sickness in thirty years. [13]

Efficacy and safety

In cell culture, fexinidazole has an IC50 of around 1–4μM against Trypanosoma brucei. [14] In the mouse model, fexinidazole cures both the first, haemolymphatic, and the second, meningoencephalitic stage of the infection, the latter at 100 mg/kg twice daily for 5 days. In patients, the clinical trials managed by DNDi and supported by Swiss TPH mainly conducted in the Democratic Republic of the Congo demonstrated that oral fexinidazole is safe and effective for use against first- and early second-stage sleeping sickness. Based on the positive opinion issued by the European Medicines Agency in 2018, the WHO has released new interim guidelines for the treatment of HAT including fexinidazole as the new therapy for first-stage and non-severe second-stage sleeping sickness caused by Trypanosoma brucei gambiense (gHAT) [15] Recently, a study of the safety and efficacy of oral fexinidazole in children with gambiense human African trypanosomiasis was accomplished and concluded that orally administered fexinidazole showed high efficacy across all stages of gambiense human African trypanosomiasis infection in children aged 6 years and older and weighing more than 20 kg. The benefit-to-risk ratio of fexinidazole for treating children with gambiense human African trypanosomiasis, regardless of disease stage, is positive. Current interventions for diagnosing, staging, and treating gambiense human African trypanosomiasis require resources, trained personnel, equipment, and hospital infrastructure. These potentially costly procedures are therefore difficult to implement in remote areas or in those that might be mired in conflict, which could prevent the goal of eliminating gambiense human African trypanosomiasis by 2030.25,26 Simplified oral treatments such as fexinidazole or single-dose oral treatments such as acoziborole (currently in clinical trials)27 that can cure both disease stages of gambiense human African trypanosomiasis and circumvent the need for systematic disease staging with lumbar puncture (a procedure associated with complications and anxiety, particularly in children28) would benefit both patients and health-care professionals [16] Furthermore, Damasio et al. evaluated the in vivo oral efficacy of self-emulsifying drug delivery systems (SEDDS) containing fexinidazole (FEX) in the experimental treatment of visceral leishmaniasis (VL). The developed FEX-SEDDS formulation presented as a clear, yellowish liquid without precipitate. In the simulated gastric and intestinal media, the FEX-SEDDS had a size of 97 ± 1 and 106 ± 9 nm, respectively. The FEX retention in droplets after SEDDS dilution in simulated gastrointestinal media was almost 100%. Antileishmanial efficacy studies showed that FEX-SEDDS was the only treatment able to significantly (p < 0.05) reduce the parasite burden in the liver and spleen of animals experimentally infected with Leishmania infantum [17]

Mechanism of action

The biologically relevant active metabolites in vivo are the sulfoxide and sulfone. [18] [19]

Synthesis

Synthetic pathway of fexinidzaole, adapted from Scheme 3 of McInturff et al. 2023. Fexinidazole synthesis.svg
Synthetic pathway of fexinidzaole, adapted from Scheme 3 of McInturff et al. 2023.

History

Fexinidazole was discovered by the German pharmaceutical company Hoechst AG, but its development as a pharmaceutical was halted in the 1980s. [21]

The US Food and Drug Administration granted the application for fexinidazole orphan drug designation. [22]

Society and culture

Fexinidazole Winthrop, a Sanofi-Aventis product developed with the Drugs for Neglected Diseases Initiative (DNDi), received a positive endorsement from the European Medicines Agency in 2018, for use in non-European markets. [23] [24] It was approved for the treatment of Trypanosoma brucei gambiense human African trypanosomiasis (HAT) in the Democratic Republic of the Congo (DRC) in December 2018. [25] Fexinidazole was included in the 'role of honour' in Préscrire magazine's 2020 prize list.Fexinidazole Winthrop° (fexinidazole) : au Tableau d'Honneur 2020

Veterinary use

Fexinidazole is promising in African animal trypanosomiasis. Torreele et al. 2010 found the drug to be effective against T. b. gambiense infection of mice, rats, rabbits and beagles. They also found no toxicity in any of them, including a lack of mutagenicity despite in vitro mutagenicity. [26]

Related Research Articles

<span class="mw-page-title-main">African trypanosomiasis</span> Parasitic disease also known as sleeping sickness

African trypanosomiasis, also known as African sleeping sickness or simply sleeping sickness, is an insect-borne parasitic infection of humans and other animals. It is caused by the species Trypanosoma brucei. Humans are infected by two types, Trypanosoma brucei gambiense (TbG) and Trypanosoma brucei rhodesiense (TbR). TbG causes over 92% of reported cases. Both are usually transmitted by the bite of an infected tsetse fly and are most common in rural areas.

<span class="mw-page-title-main">Trypanosomatida</span> Flagellate kinetoplastid excavate order

Trypanosomatida is a group of kinetoplastid unicellular organisms distinguished by having only a single flagellum. The name is derived from the Greek trypano (borer) and soma (body) because of the corkscrew-like motion of some trypanosomatid species. All members are exclusively parasitic, found primarily in insects. A few genera have life-cycles involving a secondary host, which may be a vertebrate, invertebrate or plant. These include several species that cause major diseases in humans. Some trypanosomatida are intracellular parasites, with the important exception of Trypanosoma brucei.

<span class="mw-page-title-main">Tsetse fly</span> Genus of disease-spreading insects

Tsetse are large, biting flies that inhabit much of tropical Africa. Tsetse flies include all the species in the genus Glossina, which are placed in their own family, Glossinidae. The tsetse is an obligate parasite, which lives by feeding on the blood of vertebrate animals. Tsetse has been extensively studied because of their role in transmitting disease. They have a pronounced economic impact in sub-Saharan Africa as the biological vectors of trypanosomes, causing human and animal trypanosomiasis.

<span class="mw-page-title-main">Pentamidine</span> Medical antimicrobial drug

Pentamidine is an antimicrobial medication used to treat African trypanosomiasis, leishmaniasis, Balamuthia infections, babesiosis, and to prevent and treat pneumocystis pneumonia (PCP) in people with poor immune function. In African trypanosomiasis it is used for early disease before central nervous system involvement, as a second line option to suramin. It is an option for both visceral leishmaniasis and cutaneous leishmaniasis. Pentamidine can be given by injection into a vein or muscle or by inhalation.

<span class="mw-page-title-main">Trypanosomiasis</span> Medical condition

Trypanosomiasis or trypanosomosis is the name of several diseases in vertebrates caused by parasitic protozoan trypanosomes of the genus Trypanosoma. In humans this includes African trypanosomiasis and Chagas disease. A number of other diseases occur in other animals.

<span class="mw-page-title-main">Suramin</span> Medical drug

Suramin is a medication used to treat African sleeping sickness and river blindness. It is the treatment of choice for sleeping sickness without central nervous system involvement. It is given by injection into a vein.

<i>Trypanosoma</i> Genus of parasitic flagellate protist in the Kinetoplastea class

Trypanosoma is a genus of kinetoplastids, a monophyletic group of unicellular parasitic flagellate protozoa. Trypanosoma is part of the phylum Euglenozoa. The name is derived from the Greek trypano- (borer) and soma (body) because of their corkscrew-like motion. Most trypanosomes are heteroxenous and most are transmitted via a vector. The majority of species are transmitted by blood-feeding invertebrates, but there are different mechanisms among the varying species. Trypanosoma equiperdum is spread between horses and other equine species by sexual contact. They are generally found in the intestine of their invertebrate host, but normally occupy the bloodstream or an intracellular environment in the vertebrate host.

<span class="mw-page-title-main">Melarsoprol</span> Medication used to treat sleeping sickness

Melarsoprol is an arsenic-containing medication used for the treatment of sleeping sickness. It is specifically used for second-stage disease caused by Trypanosoma brucei rhodesiense when the central nervous system is involved. For Trypanosoma brucei gambiense, eflornithine or fexinidazole is usually preferred. It is effective in about 95% of people. It is given by injection into a vein.

<span class="mw-page-title-main">Eflornithine</span> Chemical compound

Eflornithine, sold under the brand name Vaniqa among others, is a medication used to treat African trypanosomiasis and excessive hair growth on the face in women. Specifically it is used for the second stage of sleeping sickness caused by T. b. gambiense and may be used with nifurtimox. It is taken intravenously or topically. It is an ornithine decarboxylase inhibitor.

<i>Trypanosoma brucei</i> Species of protozoan parasite

Trypanosoma brucei is a species of parasitic kinetoplastid belonging to the genus Trypanosoma that is present in sub-Saharan Africa. Unlike other protozoan parasites that normally infect blood and tissue cells, it is exclusively extracellular and inhabits the blood plasma and body fluids. It causes deadly vector-borne diseases: African trypanosomiasis or sleeping sickness in humans, and animal trypanosomiasis or nagana in cattle and horses. It is a species complex grouped into three subspecies: T. b. brucei, T. b. gambiense and T. b. rhodesiense. The first is a parasite of non-human mammals and causes nagana, while the latter two are zoonotic infecting both humans and animals and cause African trypanosomiasis.

Winterbottom's sign is a swelling of lymph nodes (lymphadenopathy) along the posterior cervical lymph node chain, associated with the early phase of African trypanosomiasis, a disease caused by the parasites Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. It may be suggestive of cerebral infection. Winterbottom reported about the slave traders who, apparently aware of the ominous sign of swollen cervical lymph glands, used to palpate the necks of the slaves before buying them.

<span class="mw-page-title-main">Drugs for Neglected Diseases Initiative</span> Non-profit organization

The Drugs for Neglected Diseases initiative (DNDi) is a collaborative, patients' needs-driven, non-profit drug research and development (R&D) organization that is developing new treatments for neglected diseases, notably leishmaniasis, sleeping sickness, Chagas disease, malaria, filarial diseases, mycetoma, paediatric HIV, cryptococcal meningitis, hepatitis C, and dengue. DNDi's malaria activities were transferred to Medicines for Malaria Venture (MMV) in 2015.

<span class="mw-page-title-main">Benznidazole</span> Chemical compound

Benznidazole is an antiparasitic medication used in the treatment of Chagas disease. While it is highly effective in early disease, the effectiveness decreases in those who have long-term infection. It is the first-line treatment given its moderate side effects compared to nifurtimox. It is taken by mouth.

<span class="mw-page-title-main">Nifurtimox</span> Anti-parasitic medical drug

Nifurtimox, sold under the brand name Lampit, is a medication used to treat Chagas disease and sleeping sickness. For sleeping sickness it is used together with eflornithine in nifurtimox-eflornithine combination treatment. In Chagas disease it is a second-line option to benznidazole. It is given by mouth.

<span class="mw-page-title-main">Alan Fairlamb</span> British biochemist

Alan Hutchinson Fairlamb, CBE, FRSE, FLS, FMedSci, FRSB is a Wellcome Trust Principal Research Fellow and Professor of Biochemistry in the Division of Biological Chemistry and Drug Discovery at the School of Life Sciences, University of Dundee, Scotland. From 2006-2011 he was a member of the Scientific and Technical Advisory Committee of the Special Programme for Research and Training in Tropical Diseases (TDR) -- an independent global programme of scientific collaboration co-sponsored by UNICEF, UNDP, the World Bank and WHO. Currently he is a member of the governing board of the Tres Cantos Open Lab Foundation, whose aim is to accelerate the discovery and development of medicines to tackle diseases of the developing world in an open collaborative manner.

Wendy Gibson is Professor of Protozoology at University of Bristol, specialising in trypanosomes and molecular parasitology.

<span class="mw-page-title-main">Acoziborole</span> Antiprotozoal drug to treat sleeping sickness

Acoziborole (SCYX-7158) is an antiprotozoal drug invented by Anacor Pharmaceuticals in 2009, and now under development by the Drugs for Neglected Diseases Initiative for the treatment of African trypanosomiasis.

Nifurtimox/eflornithine is a combination of two antiparasitic drugs, nifurtimox and eflornithine, used in the treatment of African trypanosomiasis. It is included in the World Health Organization's Model List of Essential Medicines.

Victor Kande Betu Kumeso is a Congolese physician who is an expert in African trypanosomiasis. He works at the Programme National de Lutte contre la Trypanosomiase Humaine Africaine at the University of Kinshasa.

The Sleeping Sickness Commission was a medical project established by the British Royal Society to investigate the outbreak of African sleeping sickness or African trypanosomiasis in Africa at the turn of the 20th century. The outbreak of the disease started in 1900 in Uganda, which was at the time a protectorate of the British Empire. The initial team in 1902 consisted of Aldo Castellani and George Carmichael Low, both from the London School of Hygiene and Tropical Medicine, and Cuthbert Christy, a medical officer on duty in Bombay, India. From 1903, David Bruce of the Royal Army Medical Corps and David Nunes Nabarro of the University College Hospital took over the leadership. The commission established that species of blood protozoan called Trypanosoma brucei, named after Bruce, was the causative parasite of sleeping sickness.

References

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  8. ↑ Mowbray CE (2017). "Antileishmanial Drug Discovery: Past, Present, and Future Perspectives". In Gil C, Rivas L (eds.). Drug Discovery for Leishmaniasis. Royal Society of Chemistry. p. 30. ISBN   9781788012584.
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  13. ↑ Torreele E, Bourdin Trunz B, Tweats D, Kaiser M, Brun R, Mazué G, et al. (December 2010). Boelaert M (ed.). "Fexinidazole--a new oral nitroimidazole drug candidate entering clinical development for the treatment of sleeping sickness". PLOS Neglected Tropical Diseases. 4 (12): e923. doi: 10.1371/journal.pntd.0000923 . PMC   3006138 . PMID   21200426.
  14. ↑ Kaiser M, Bray MA, Cal M, Bourdin Trunz B, Torreele E, Brun R (December 2011). "Antitrypanosomal activity of fexinidazole, a new oral nitroimidazole drug candidate for treatment of sleeping sickness". Antimicrobial Agents and Chemotherapy. 55 (12). American Society for Microbiology: 5602–5608. doi:10.1128/aac.00246-11. PMC   3232772 . PMID   21911566.
  15. ↑ Bernhard S, Kaiser M, Burri C, Mäser P (October 2022). "Fexinidazole for Human African Trypanosomiasis, the Fruit of a Successful Public-Private Partnership". Diseases. 10 (4): 90. doi: 10.3390/diseases10040090 . PMC   9589988 . PMID   36278589.
  16. ↑ Kande Betu Kumesu V, Mutombo Kalonji W, Bardonneau C, Valverde Mordt O, Ngolo Tete D, Blesson S, et al. (November 2022). "Safety and efficacy of oral fexinidazole in children with gambiense human African trypanosomiasis: a multicentre, single-arm, open-label, phase 2-3 trial". The Lancet. Global Health. 10 (11): e1665–e1674. doi:10.1016/S2214-109X(22)00338-2. PMC   9554014 . PMID   36179736.
  17. ↑ Damasio DS, Antunes PA, Lages EB, Morais-Teixeira E, Vital KD, Cardoso VN, et al. (January 2023). "A new oral self-emulsifying drug delivery system improves the antileishmania efficacy of fexinidazole in vivo". International Journal of Pharmaceutics. 631: 122505. doi:10.1016/j.ijpharm.2022.122505. PMID   36549405. S2CID   254917177.
  18. ↑ Wyllie S, Patterson S, Stojanovski L, Simeons FR, Norval S, Kime R, et al. (February 2012). "The anti-trypanosome drug fexinidazole shows potential for treating visceral leishmaniasis". Science Translational Medicine. 4 (119): 119re1. doi:10.1126/scitranslmed.3003326. PMC   3457684 . PMID   22301556.
  19. ↑ Sokolova AY, Wyllie S, Patterson S, Oza SL, Read KD, Fairlamb AH (July 2010). "Cross-resistance to nitro drugs and implications for treatment of human African trypanosomiasis". Antimicrobial Agents and Chemotherapy. 54 (7): 2893–2900. doi:10.1128/AAC.00332-10. PMC   2897277 . PMID   20439607.
  20. ↑ McInturff EL, France SP, Leverett CA, Flick AC, Lindsey EA, Berritt S, et al. (August 2023). "Synthetic Approaches to the New Drugs Approved During 2021". Journal of Medicinal Chemistry. 66 (15). American Chemical Society (ACS): 10150–10201. doi:10.1021/acs.jmedchem.3c00501. PMID   37528515. S2CID   260377572.
  21. ↑ McNeil Jr D (8 January 2008). "Jump-Start on Slow Trek to Treatment for a Disease". The New York Times .
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  25. ↑ "Fexinidazole, the first all-oral treatment for sleeping sickness, approved in Democratic Republic of Congo". Drugs for Neglected Diseases Initiative (DNDi). 29 January 2019. Retrieved 4 June 2019.
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