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Fexinidazole

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Fexinidazole
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
PubChemCID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard100.207.619Edit this at Wikidata
Chemical and physical data
FormulaC12H13N3O3S
Molar mass279.31g·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

Fexinidazoleis amedicationused to treatAfrican trypanosomiasis(sleeping sickness) caused byTrypanosoma brucei gambiense.[3]It is effective against both first and second stage disease.[3]Also a potential new treatment forChagas disease,aneglected tropical diseasethat affects millions of people worldwide.[4]It is taken by mouth.[5]

Common side effects include nausea, vomiting, headache, and trouble sleeping.[6]Other side effects may includeQT prolongation,psychosis,andlow white blood cells.[7]It is unclear if use duringpregnancyorbreast feedingis safe.[7]Fexinidazole is in theantiparasiticand thenitroimidazolefamily 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 theEuropean Medicines Agencyin 2018.[6]It is on theWorld Health Organization's List of Essential Medicines.[9][10]Development for sleeping sickness was funded by theDrugs for Neglected Diseases initiativein collaboration withSanofi.[11]Fexinidazole was approved for medical use in the United States in July 2021.[1]

Medical use

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Sleeping sickness

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A trial in Africa found fexinidazole to be 91% effective at treating sleeping sickness.[6][12]Though less effective thannifurtimoxwitheflornithinein 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

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In cell culture, fexinidazole has anIC50of around 1–4 μM againstTrypanosoma brucei.[14]In the mouse model, fexinidazole cures both the first, hemolymphatic, 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 theDemocratic Republic of the Congodemonstrated 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 byTrypanosoma 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.[16][17]

Simplified oral treatments such as fexinidazole or single-dose oral treatments such asacoziborole(currently in clinical trials) 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[18] Furthermore, Damasioet al.evaluated thein vivooral efficacy of self-emulsifying drug delivery systems (SEDDS) containing fexinidazole 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 withLeishmania infantum.[19]

Mechanism of action

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The biologically relevant active metabolitesin vivoare thesulfoxideandsulfone.[20][21]

History

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Fexinidazole was discovered by the German pharmaceutical companyHoechst AG,but its development as a pharmaceutical was halted in the 1980s.[22]

The USFood and Drug Administrationgranted the application for fexinidazoleorphan drugdesignation.[23]

Society and culture

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Fexinidazole Winthrop, aSanofi-Aventis product developed with theDrugs for Neglected Diseases Initiative(DNDi), received a positive endorsement from theEuropean Medicines Agencyin 2018, for use in non-European markets.[24][25]It was approved for the treatment ofTrypanosoma brucei gambiensehuman African trypanosomiasis (HAT) in the Democratic Republic of the Congo (DRC) in December 2018.[26]Fexinidazole was included in the 'role of honour' in Préscrire magazine's 2020 prize list.[27]

Veterinary use

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Fexinidazole is promising inAfrican animal trypanosomiasis.Torreeleet al.[citation needed]found the drug to be effective againstT. b. gambienseinfection ofmice,rats,rabbitsandbeagles.They also found no toxicity in any of them, including a lack ofmutagenicitydespitein vitromutagenicity.[17]

Synthesis

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Fexinidazole can besynthesizedin several steps fromnitroimidazole.[28]

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

References

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  1. ^ab"Fexinidazole: FDA-Approved Drugs".U.S. Food and Drug Administration.Retrieved16 July2021.
  2. ^"Fexinidazole tablet".DailyMed.U.S. National Library of Medicine.Retrieved20 August2021.
  3. ^ab"Fexinidazole Winthrop H-W-2320".European Medicines Agency.22 January 2019. Archived fromthe originalon 18 January 2021.Retrieved12 November2019.
  4. ^Torrico F, Gascón J, Ortiz L, Pinto J, Rojas G, Palacios A, et al. (February 2023)."A Phase 2, Randomized, Multicenter, Placebo-Controlled, Proof-of-Concept Trial of Oral Fexinidazole in Adults With Chronic Indeterminate Chagas Disease".Clinical Infectious Diseases.76(3): e1186–e1194.doi:10.1093/cid/ciac579.PMC9907522.PMID35925555.
  5. ^abDeeks ED (February 2019). "Fexinidazole: First Global Approval".Drugs.79(2): 215–220.doi:10.1007/s40265-019-1051-6.PMID30635838.S2CID57772417.
  6. ^abcde"Fexinidazole Winthrop (fexinidazole)"(PDF).EMA.Archived fromthe original(PDF)on 2 January 2021.Retrieved12 November2019.
  7. ^ab"Fexinidazole Winthrop"(PDF).EMA.Archived fromthe original(PDF)on 12 November 2019.Retrieved12 November2019.
  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.ISBN9781788012584.
  9. ^World Health Organization(2019).World Health Organization model list of essential medicines: 21st list 2019.Geneva: World Health Organization.hdl:10665/325771.WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  10. ^World Health Organization(2021).World Health Organization model list of essential medicines: 22nd list (2021).Geneva: World Health Organization.hdl:10665/345533.WHO/MHP/HPS/EML/2021.02.
  11. ^"Fexinidazole – DNDi".dndi.org.31 December 2004.Retrieved12 November2019.
  12. ^Mesu VK, Kalonji WM, Bardonneau C, Mordt OV, Blesson S, Simon F, et al. (January 2018)."Oral fexinidazole for late-stage African Trypanosoma brucei gambiense trypanosomiasis: a pivotal multicentre, randomised, non-inferiority trial".Lancet.391(10116): 144–154.doi:10.1016/s0140-6736(17)32758-7.PMID29113731.S2CID46781585.
  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.PMC3006138.PMID21200426.
  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.PMC3232772.PMID21911566.
  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.PMC9589988.PMID36278589.
  16. ^"Fexinidazole, the first all-oral treatment for sleeping sickness, approved in Democratic Republic of Congo".Drugs for Neglected Diseases Initiative (DNDi).29 January 2019.Retrieved4 June2019.
  17. ^abKennedy PG (February 2013). "Clinical features, diagnosis, and treatment of human African trypanosomiasis (sleeping sickness)".The Lancet. Neurology.12(2).Elsevier:186–194.doi:10.1016/s1474-4422(12)70296-x.PMID23260189.S2CID8688394.
  18. ^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.PMC9554014.PMID36179736.
  19. ^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.PMID36549405.S2CID254917177.
  20. ^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.PMC3457684.PMID22301556.
  21. ^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.PMC2897277.PMID20439607.
  22. ^McNeil Jr D(8 January 2008)."Jump-Start on Slow Trek to Treatment for a Disease".The New York Times.
  23. ^Advancing Health Through Innovation: New Drug Therapy Approvals 2021(PDF).U.S.Food and Drug Administration(FDA)(Report). 13 May 2022.Archivedfrom the original on 6 December 2022.Retrieved22 January2023.Public DomainThis article incorporates text from this source, which is in thepublic domain.
  24. ^"CHMP Summary of Opinion - Fexinidazole Winthrop"(PDF).Retrieved19 November2018.
  25. ^McNeil Jr D(16 November 2018)."Rapid Cure Approved for Sleeping Sickness, a Horrific Illness".The New York Times.Retrieved20 November2018.
  26. ^"Fexinidazole, the first all-oral treatment for sleeping sickness, approved in Democratic Republic of Congo".Drugs for Neglected Diseases Initiative (DNDi).29 January 2019.Retrieved4 June2019.
  27. ^"Fexinidazole Winthrop° (fexinidazole): au Tableau d'Honneur 2020".
  28. ^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.PMID37528515.S2CID260377572.
[edit]
  • "Fexinidazole".Drug Information Portal.U.S. National Library of Medicine.
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