{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T02:47:22Z","timestamp":1789786042327,"version":"4.0.1"},"reference-count":61,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,1,21]],"date-time":"2022-01-21T00:00:00Z","timestamp":1642723200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Human African trypanosomiasis (HAT or \u2018sleeping sickness\u2019) is a neglected tropical disease. If untreated, it is always fatal and leads to death. A few treatments are available for HAT, but most of them require a skilled professional, which increases the financial burden on the patient. Recently, fexinidazole (FEX) has been approved by the European Medicine Agency (EMA) and the United States Food and Drug Administration (USFDA) as the first all-oral therapy for the treatment of stage-1 (hemolymphatic) as well as stage-2 (meningoencephalitic) of HAT. Before the FEX approval, there were separate treatments for stage-1 and stage-2 of HAT. This study reviews the discovery, development timeline, inventions, and patent literature of FEX. It was first approved by EMA and USFDA in 2018 and 2021, respectively. FEX was also added to the World Health Organization\u2019s list of essential drugs in 2019. The patent literature search revealed many types of patents\/patent applications (compound, salt, process, method of treatment, drug combinations, and compositions) related to FEX, which have been summarized in this article. The authors foresee a great scope to develop more inventions based on FEX (novel salts, polymorphs, drug conjugates, cyclodextrin complex, etc.) for the treatment of many protozoal diseases (Leishmaniasis and Chagas disease), inflammatory diseases, and other microbial infections. New combinations of FEX with other treatments of HAT may also provide fruitful results. This review might be useful to the scientists working on the HAT and other neglected diseases to develop novel inventions and innovations of therapeutic relevance.<\/jats:p>","DOI":"10.3390\/ph15020128","type":"journal-article","created":{"date-parts":[[2022,1,23]],"date-time":"2022-01-23T20:34:40Z","timestamp":1642970080000},"page":"128","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Discovery, Development, Inventions and Patent Review of Fexinidazole: The First All-Oral Therapy for Human African Trypanosomiasis"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6064-1040","authenticated-orcid":false,"given":"Mohd","family":"Imran","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Northern Border University, Rafha 91911, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0729-3403","authenticated-orcid":false,"given":"Shah Alam","family":"Khan","sequence":"additional","affiliation":[{"name":"College of Pharmacy, National University of Science and Technology, Muscat 130, Oman"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6687-0461","authenticated-orcid":false,"given":"Mohammed Kanan","family":"Alshammari","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Care, Rafha Central Hospital, North Zone, Rafha 91911, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashwaq Muiedh","family":"Alqahtani","sequence":"additional","affiliation":[{"name":"Orange Pharmacies, Riyadh 13248, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Turkiah Abdullah","family":"Alanazi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Care, King Fahd Specialist Hospital, Tabuk 47717, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3585-0828","authenticated-orcid":false,"given":"Mehnaz","family":"Kamal","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Talha","family":"Jawaid","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Medicine, Al Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 13317, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9179-4373","authenticated-orcid":false,"given":"Mohammed M.","family":"Ghoneim","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University, Ad Diriyah 13713, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0922-9819","authenticated-orcid":false,"given":"Sultan","family":"Alshehri","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6109-0885","authenticated-orcid":false,"given":"Faiyaz","family":"Shakeel","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"E1498","DOI":"10.1016\/S1473-3099(21)00635-6","article-title":"WHO manual on neglected tropical diseases","volume":"21","author":"Bagcchi","year":"2021","journal-title":"Lancet Infect. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2334","DOI":"10.1007\/s00415-019-09425-7","article-title":"Update on human African trypanosomiasis (sleeping sickness)","volume":"266","author":"Kennedy","year":"2019","journal-title":"J. Neurol."},{"key":"ref_3","unstructured":"Costi, M.P., Costantino, L., Ferrari, S., Linciano, P., and Da Silva, A.C. (2020). Triaminopyrimidine Derivatives with Antiparasitic Activity. (WO2020188437A1)."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/S1474-4422(12)70296-X","article-title":"Clinical features, diagnosis, and treatment of human African trypanosomiasis (sleeping sickness)","volume":"12","author":"Kennedy","year":"2013","journal-title":"Lancet Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2397","DOI":"10.1016\/S0140-6736(17)31510-6","article-title":"Human African trypanosomiasis","volume":"390","author":"Cecchi","year":"2017","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1172\/JCI200421052","article-title":"Human African trypanosomiasis of the CNS: Current issues and challenges","volume":"113","author":"Kennedy","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Bisser, S., Lumbala, C., Nguertoum, E., Kande, V., Flevaud, L., Vatunga, G., Boelaert, M., B\u00fcscher, P., Josenando, T., and Bessell, P.R. (2016). Sensitivity and specificity of a prototype rapid diagnostic test for the detection of Trypanosoma brucei gambiense infection: A multi-centric prospective study. PLoS Negl. Trop. Dis., 10.","DOI":"10.1371\/journal.pntd.0004608"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Lumbala, C., Bi\u00e9ler, S., Kayembe, S., Makabuza, J., Ongarello, S., and Ndung\u2019u, J.M. (2018). Prospective evaluation of a rapid diagnostic test for Trypanosoma brucei gambiense infection developed using recombinant antigens. PLoS Negl. Trop. Dis., 12.","DOI":"10.1371\/journal.pntd.0006386"},{"key":"ref_9","unstructured":"Hafiz, S., and Kyriakopoulos, C. (2021, December 20). Pentamidine. 19 June 2021, StatPearls, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK557586\/."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e01168-19","DOI":"10.1128\/AAC.01168-19","article-title":"100 years of Suramin","volume":"64","author":"Wiedemar","year":"2020","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1358\/dot.2021.57.4.3251712","article-title":"Update on nifurtimox for treatment of Chagas disease","volume":"57","author":"Thakare","year":"2021","journal-title":"Drugs Today"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"365","DOI":"10.4103\/0378-6323.35752","article-title":"Eflornithine","volume":"73","author":"Jobanputra","year":"2007","journal-title":"Indian J. Dermatol. Venereol. Leprol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/j.pt.2018.04.002","article-title":"Melarsoprol resistance in African trypanosomiasis","volume":"34","author":"Fairlamb","year":"2018","journal-title":"Trends Parasitol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Hidalgo, J., Ortiz, J.F., Fabara, S.P., Eissa-Garc\u00e9s, A., Reddy, D., Collins, K.D., and Tirupathi, R. (2021). Efficacy and toxicity of fexinidazole and nifurtimox plus eflornithine in the treatment of African trypanosomiasis: A systematic review. Cureus, 13.","DOI":"10.7759\/cureus.16881"},{"key":"ref_15","unstructured":"(2021, November 02). Developing Products for Rare Diseases & Conditions, Available online: https:\/\/www.accessdata.fda.gov\/scripts\/opdlisting\/oopd\/detailedIndex.cfm?cfgridkey=513915."},{"key":"ref_16","unstructured":"(2021, November 02). Prescribing Information of Fexinidazole, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2021\/214429s000lbl.pdf."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1358\/dot.2019.55.11.3068795","article-title":"Fexinidazole for the treatment of human African trypanosomiasis","volume":"55","author":"Fairlamb","year":"2019","journal-title":"Drugs Today"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Neau, P., H\u00e4nel, H., Lameyre, V., Strub-Wourgaft, N., and Kuykens, L. (2020). Innovative partnerships for the elimination of human African Trypanosomiasis and the development of fexinidazole. Trop. Med. Infect. Dis., 5.","DOI":"10.3390\/tropicalmed5010017"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1007\/s40265-019-1051-6","article-title":"Fexinidazole: First global approval","volume":"79","author":"Deeks","year":"2019","journal-title":"Drugs"},{"key":"ref_20","unstructured":"(2021, November 02). Quality Review of Fexinidazole, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2021\/214429Orig1s000ChemR.pdf."},{"key":"ref_21","unstructured":"Erhardt, W., and Wolfgang, R. (1977). 1-Methyl-2-(phenyl-oxymethyl)-5-nitro-imidazoles and Process for Their Manufacture. (US4042705A), U.S. Patent."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Torreele, E., Bourdin Trunz, B., Tweats, D., Kaiser, M., Brun, R., Mazue, G., Bray, M.A., and Pecoul, B. (2010). Fexinidazole\u2014A new oral nitroimidazole drug candidate entering clinical development for the treatment of sleeping sickness. PLoS Negl. Trop. Dis., 4.","DOI":"10.1371\/journal.pntd.0000923"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"119re1","DOI":"10.1126\/scitranslmed.3003326","article-title":"The anti-trypanosome drug fexinidazole shows potential for treating visceral leishmaniasis","volume":"4","author":"Wyllie","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.pt.2014.04.003","article-title":"Nitro drugs for the treatment of trypanosomatid diseases: Past, present, and future prospects","volume":"30","author":"Patterson","year":"2014","journal-title":"Trends Parasitol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1007\/s40262-014-0136-3","article-title":"Determination of an optimal dosing regimen for fexinidazole, a novel oral drug for the treatment of human African trypanosomiasis: First-in-human studies","volume":"53","author":"Tarral","year":"2014","journal-title":"Clin. Pharmacokinet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5602","DOI":"10.1128\/AAC.00246-11","article-title":"Antitrypanosomal activity of fexinidazole, a new oral nitroimidazole drug candidate for treatment of sleeping sickness","volume":"55","author":"Kaiser","year":"2011","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_27","unstructured":"(2021, November 06). Clinical Trials on Fexinidazole, Available online: htttps:\/\/clinicaltrial.gov."},{"key":"ref_28","unstructured":"(2021, November 06). Espacenet Database. Available online: https:\/\/worldwide.espacenet.com\/patent\/search."},{"key":"ref_29","unstructured":"(2021, November 06). USPTO Full Text-Image Database, Available online: https:\/\/patft.uspto.gov\/netahtml\/PTO\/search-bool.html."},{"key":"ref_30","unstructured":"(2021, November 06). Patenetscope Database. Available online: https:\/\/patentscope.wipo.int\/search\/en\/search.jsf."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1021\/ci050481b","article-title":"SciFinder Scholar 2006: An empirical analysis of research topic query processing","volume":"46","author":"Wagner","year":"2006","journal-title":"J. Chem. Inf. Model"},{"key":"ref_32","unstructured":"Erhardt, W. (1980). Process for the Manufacture of 1-alkyl-2-(phenoxymethyl)-5-nitroimidazoles. (CA1079738A)."},{"key":"ref_33","unstructured":"Parkanyi, Z., Alattyani, E., Bugir, Z., and Harsanyi, M. (2017). Method for Preparing Phenyloxymethyl-Nitro-Imidazole Derivatives and Use of Same. (US9758488B2), U.S. Patent."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"10498","DOI":"10.1021\/acs.joc.5b02133","article-title":"Silver(I)-Promoted ipso-nitration of carboxylic acids by nitronium tetrafluoroborate","volume":"80","author":"Natarajan","year":"2015","journal-title":"J. Org. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1016\/j.bmcl.2010.12.040","article-title":"Compounds containing 2-substituted imidazole ring for treatment against human African trypanosomiasis","volume":"21","author":"Samant","year":"2011","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_36","unstructured":"Pollmeier, M., and Blair, J.L. (2017). Method for Treating and Curing Leishmaniosis Using Fexinidazole. (US9585871B2), U.S. Patent."},{"key":"ref_37","unstructured":"Blake, D., Naughton, D., Stratford, I., and Adams, G. (1999). Treatment of Inflammatory Conditions. (WO9912547A1)."},{"key":"ref_38","unstructured":"Blake, D., Naughton, D., Stratford, I., and Adams, G. (1999). Treatment of Inflammatory Conditions. (WO9912548A1)."},{"key":"ref_39","unstructured":"Xiao, Z., Yu, D.X., Pouton, C.W., and He, Z. (2021). Nitroimidazole Formulations. (US2021220335A1), U.S. Patent."},{"key":"ref_40","unstructured":"Fairlamb, A., Patterson, S., Wylie, S., and Read, K. (2017). Treatment of Parasitic Disease. (WO2017072523A1)."},{"key":"ref_41","unstructured":"Page, S., Stevens, A., McCluskey, A., Keenan, M., and Abraham, R. (2019). Methods for Treating Protozoan Infections. (US10392363B2), U.S. Patent."},{"key":"ref_42","unstructured":"Page, S., Stevens, A., McCluskey, A., Keenan, M., and Abraham, R. (2020). Methods for Treating Protozoan Infections. (US10562880B2), U.S. Patent."},{"key":"ref_43","unstructured":"Page, S., Stevens, A., McCluskey, A., Keenan, M., and Abraham, R. (2020). Methods for Treating Protozoan Infections. (US10752606B2), U.S. Patent."},{"key":"ref_44","unstructured":"Jiricek, J., Ng, S.P., and Rao, S.P.S. (2019). Cyanotriazole Compounds and Uses Thereof. (WO2019244049A1)."},{"key":"ref_45","unstructured":"Lellouche, J.P., Michaeli, S., Israel, L.L., Harel, Y., Dolitzky, A., and Ostrovsky, S. (2019). Core-Shell Particles Comprising Metal Oxide and Lanthanide Element. (WO2019043701A1)."},{"key":"ref_46","unstructured":"Carricarte, V., and Roldan, E. (2021). Nanostructured Nanoparticles Comprising One or More Active Ingredients for the Treatment of Diseases Caused by Trypanosomes and for the Treatment of Tumours of Neural Origin, Compositions Comprising Same, a Preparation Method and Therapeutic Use Thereof. (US2021322329A1), U.S. Patent."},{"key":"ref_47","unstructured":"Scott, E.A., Yi, S., Karabin, N., and Li, X. (2021). Compositions and Methods of Using Propylene Sulfide-Based Polymers for Treatment of Chagas Disease. (US2021052498A1), U.S. Patent."},{"key":"ref_48","unstructured":"Patterson, J. (2021). Engineered Platelets for Targeted Delivery of a Therapeutic Agent. (WO2021123775A3)."},{"key":"ref_49","unstructured":"Brennan, A.B., Long, C.J., Bagan, J.W., Schumacher, J.F., and Spiecker, M.M. (2015). Surface Topographies for Non-Toxic Bioadhesion Control. (US9016221B2), U.S. Patent."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"De Koning, H.P. (2020). The drugs of sleeping sickness: Their mechanisms of action and resistance, and a brief history. Trop. Med. Infect. Dis., 5.","DOI":"10.3390\/tropicalmed5010014"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.idc.2018.10.003","article-title":"Human African trypanosomiasis: Progress and stagnation","volume":"33","author":"Bottieau","year":"2019","journal-title":"Infect. Dis. Clin. N. Am."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/j.amjsurg.2020.06.021","article-title":"The effect of trauma center verification level on traumatic brain injury outcome after implementation of the orange book","volume":"221","author":"Plurad","year":"2021","journal-title":"Am. J. Surg."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Imran, M., Kumar Arora, M., Asdaq, S.M., Khan, S.A., Alaqel, S.I., Alshammari, M.K., Alshehri, M.M., Alshrari, A.S., Mateq Ali, A., and Al-Shammeri, A.M. (2021). Discovery, development, and patent trends on molnupiravir: A prospective oral treatment for COVID-19. Molecules, 26.","DOI":"10.3390\/molecules26195795"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Imran, M., Asdaq, S.M., Khan, S.A., Unnikrishnan Meenakshi, D., Alamri, A.S., Alsanie, W.F., Alhomrani, M., Mohzari, Y., Alrashed, A., and AlMotairi, M. (2021). Innovations and patent trends in the development of USFDA approved protein kinase inhibitors in the last two decades. Pharmaceuticals, 14.","DOI":"10.3390\/ph14080710"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1016\/j.jiph.2021.06.013","article-title":"Trends in the development of remdesivir based inventions against COVID-19 and other disorders: A patent review","volume":"14","author":"Imran","year":"2021","journal-title":"J. Infect. Public Health"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Rodgers, J., Jones, A., Gibaud, S., Bradley, B., McCabe, C., Barrett, M.P., Gettinby, G., and Kennedy, P.G. (2011). Melarsoprol cyclodextrin inclusion complexes as promising oral candidates for the treatment of human African trypanosomiasis. PLoS Negl. Trop. Dis., 5.","DOI":"10.1371\/journal.pntd.0001308"},{"key":"ref_57","unstructured":"(2021, January 12). Medicines for the People. Available online: https:\/\/dndi.org\/wp-content\/uploads\/2021\/08\/DNDi-AnnualReport-2020.pdf."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1017\/S0031182020000645","article-title":"Human African trypanosomiasis: The current situation in endemic regions and the risks for non-endemic regions from imported cases","volume":"147","author":"Gao","year":"2020","journal-title":"Parasitology"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1186\/s40249-018-0444-1","article-title":"Innovation in neglected tropical disease drug discovery and development","volume":"7","author":"Weng","year":"2018","journal-title":"Infect. Dis. Poverty"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Dickie, E.A., Giordani, F., Gould, M.K., M\u00e4ser, P., Burri, C., Mottram, J.C., Rao, S.P., and Barrett, M.P. (2020). New drugs for human African trypanosomiasis: A twenty first century success story. Trop. Med. Infect. Dis., 5.","DOI":"10.3390\/tropicalmed5010029"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"105","DOI":"10.4103\/0972-9062.310860","article-title":"Accelerating towards human African trypanosomiasis elimination: Issues and opportunities","volume":"57","author":"Ozioko","year":"2020","journal-title":"J. Vector Borne Dis."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/2\/128\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:05:44Z","timestamp":1760133944000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/2\/128"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,21]]},"references-count":61,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["ph15020128"],"URL":"https:\/\/doi.org\/10.3390\/ph15020128","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,21]]}}}