Discovery, Development, Inventions and Patent Review of Fexinidazole: The First All-Oral Therapy for Human African Trypanosomiasis
Abstract
:1. Introduction
2. Fexinidazole (FEX)
3. Pharmacology of FEX
4. Clinical Trials on FEX
Condition | Phase (Number Enrolled) | Status (Study Start Date (SSD); Study Completion Date (SCD); Last Update Date (LUD)) | National Clinical Trial (NCT) Number/Other IDs (Sponsor/Collaborators; Funder Type; Location) |
---|---|---|---|
Chagas Disease and South American Trypanosomiasis | Phase 2 (140) | Unknown (SSD: July 2014; SCD: February 2016; LUD: 15 July 2015) | NCT02498782/DNDi-CH-FEXI-001 (Drugs for Neglected Diseases initiative; Other; Bolivia) |
Trypanosomiasis (African) | Phase 1 (30) | Terminated (SSD: September 2011; SCD: February 2012; LUD: 31 March 2017) | NCT01483170/DNDiFEX003 (Drugs for Neglected Diseases initiative; Other; France) |
Visceral Leishmaniasis | Phase 2 (14) | Terminated (SSD: November 2013; SCD: September 2015; LUD: 30 October 2015) | NCT01980199/FEXI VL001 (Drugs for Neglected Diseases initiative; Other; Sudan) |
r-Human African Trypanosomiasis | Phase 2/3 (50) | Recruiting (SSD: 29 September 2019; SCD: March 2023; LUD: 30 August 2021) | NCT03974178/DNDi-FEX-07-HAT (Drugs for Neglected Diseases initiative; Other; Malawi and Uganda) |
Trypanosomiasis (African) | Phase 1 (30) | Completed (SSD: March 2015; SCD: June 2015; LUD: 8 October 2015) | NCT02571062/DNDiHATFEX008 (Drugs for Neglected Diseases initiative; Other; France) |
Human African Trypanosomiasis | Phase 2/3 (394) | Completed (SSD: October 2012; SCD: 26 April 2017; LUD: 20 February 2018) | NCT01685827/DNDiFEX004 (Drugs for Neglected Diseases initiative; Other; Batangafo, Bagata, Congo, etc.) |
Human African Trypanosomiasis | Phase 2/3 (125) | Completed (SSD: May 3, 2014; SCD: 27 June 2017; LUD: 24 June 2020) | NCT02184689/DNDiHATFEX006 (Drugs for Neglected Diseases initiative; Other; Congo) |
Human African Trypanosomiasis | Phase 2/3 (230) | Completed (SSD: 30 April 2014; SCD: 25 April 2017; LUD: 24 June 2020) | NCT02169557/DNDiHATFEX005 (Drugs for Neglected Diseases initiative; Other; Congo) |
Human African Trypanosomiasis | Phase 1 (108) | Completed (SSD: September 2009; SCD: October 2010; LUD: 6 April 2017) | NCT00982904/DNDiFEX001 (Drugs for Neglected Diseases initiative and Sanofi; Other/Industry; France) |
Human African Trypanosomiasis and Trypanosomiasis (Gambian) | Phase 3 (174) | Completed (SSD: 17 November 2016; SCD: 1 February 2021; LUD: 11 October 2021) | NCT03025789/DNDi-FEX-09-HAT (Drugs for Neglected Diseases initiative and Sanofi; Other/Industry; Congo, Mbuji-Mayi, Bagata, etc.) |
Pharmacokinetic in Healthy Volunteers | Phase 1 (12) | Completed (SSD: February 2011; SCD: April 2011; LUD: 31 March 2017) | NCT01340157/DNDiFEX002 (Drugs for Neglected Diseases initiative and Sanofi; Other/Industry; France) |
Chagas’ Disease (Chronic) | Phase 2 (45) | Completed (SSD: 13 November 2017; SCD: 28 August 2019; LUD: 23 September 2020) | NCT03587766/DNDi-FEX-12-CH (Drugs for Neglected Diseases initiative; Other; Spain) |
5. Patent Searching
6. Patent Analysis
6.1. Compound Patent
6.2. Process Patents
6.3. Patents/Applications Related to the Method of Treatment
6.4. Patents/Applications Related to the Combination of FEX with Other Molecules
6.5. Patents/Applications Related to Novel Compositions of FEX
7. Conclusions
8. Expert Opinion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Drug (Dosage Form and Administration) | Comments |
---|---|
Treatment of Stage 1 of Human African Trypanosomiasis | |
Pentamidine (Solution for inhalation/Injection) | A skilled and trained professional is needed for drug administration. It is administered as a single daily intramuscular/intravenous injection for seven days. It can cause severe hypotension after intramuscular/intravenous administration, hypoglycemia, acute pancreatitis, and cardiac arrhythmias, and is effective against stage-1 of g-human African trypanosomiasis only because it does not cross the blood–brain barrier efficiently [9]. |
Suramin (Intravenous, injection) | A skilled and trained professional is needed for drug administration. It is mainly used for stage-1 of r-human African trypanosomiasis, and rarely used for stage-1 g-human African trypanosomiasis. It can cause renal toxicity and anaphylactic reactions [10]. |
Treatment of Stage 2 of Human African Trypanosomiasis | |
Nifurtimox (Tablet, Oral) | The combination of nifurtimox with eflornithine is the first-line treatment for stage-2 of human African trypanosomiasis. It has potential for genotoxicity, carcinogenicity, fetal toxicity, worsening of neurological and psychiatric conditions, hypersensitivity, decreased appetite and weight loss, and porphyria [11]. |
Eflornithine (Intravenous, injection) | A skilled and trained professional is needed for drug administration and requires long therapy. It can cause fever, pruritus, hypertension, cough, anorexia, nausea, vomiting, diarrhea, abdominal pain, headaches, and is the second-line treatment for stage-2 of g-human African trypanosomiasis [12]. |
Melarosoprol (Intravenous, injection) | A skilled and trained professional is needed for drug administration and is effective for stage-2 g-human African trypanosomiasis. Its administration is painful and toxic. The adverse events may be life-threatening including encephalopathic syndrome [13]. |
Nifurtimox-eflornithine combination therapy (Oral Nifurtimox + Intravenous Eflornithine) | A skilled and trained professional is needed for drug administration. It needs systematic hospitalization and is mainly used for stage-2 of g-human African trypanosomiasis [14]. |
Proprietary Name (Application Number; Applicant) | Dosage Form; Route; Strength | Marketing Status (Exclusivities) | Recommended Dosage | |
---|---|---|---|---|
Greater than or Equal to 35 kg | Greater than or Equal to 20 and Less than 35 kg | |||
Fexinidazole (N214429; Sanofi Aventis) | Immediate release tablet; Oral; 600 mg | Prescription (New Chemical Entity (NCE) and Orphan Drug Exclusivity (ODE-359) expiring on 16 July 2026, and 16 July 2028, respectively) | Loading dose (1800 mg, 3 tablets) for four days followed by the maintenance dose (1200 mg, 2 tablets) for 6 days | Loading dose (1200 mg, 2 tablets) for four days followed by the maintenance dose (600 mg, 1 tablet) for 6 days |
Patent/Patent Application Number (Assignee; Publication Date; Priority Country; Estimated Expiry Date) | Legal Status on 6 November 2021 (International Patent Classification) | Family Members on 6 November 2021 |
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US4042705A (Hoechst AG; August 16, 1977; Germany; Expired) | Expired patent (A61K31/415, A61P31/04, C07D233/94, (IPC1-7): A61K31/415, C07D233/94) | AT359059B, AU500640B2, CH605813A5, CH605819A5, DK142412C, EG12284A, ES449589A1, FI61185C, FR2317925B1, GB1541280A, GR66090B, HU173463B, IE43692B1, IL50023A, IT1064924B, JPS5231074A, LU75359A1, MX3539E, MY8100120A, NL7607495A, NO145136B, NO145136C, NZ181421A, PT65350B, SE414927B |
CA1079738A (Hoechst AG; 17 June 1980; Germany; Expired) | Expired patent (C07D233/94, (IPC1-7): C07D233/94) | AT361468B, ATA128477A, CH624942A5, DK144524C, EG13828A, ES456117A2, FI770599A, IT1115608B, LU76834A1, NL7701838A, NO770648L, SE7702126L |
US9758488B2 (Sanofi; 12 September 2017; Europe; 24 December 2032) | Patented case (C07D233/94) | AP3759A, BR112015011446A2, CA2892334C, CN104797562B, CR20150286A, CY1118983T1, ECSP15025960A, EP2922822B1, ES2618800T3, HRP20170390T1, HUE032160T2, IL238934A, MX365587B, PL2922822T3, SG11201504047TA, SI2922822T1, WO2014079497A1, ZA201503063B |
US9585871B2 (Merial Limited; 7 March 2017; USA; 31 January 2034) | Patented case (A61K31/4164) | AU2014212217B2, CY1120381T1, DK2950795T3, EP2950795B1, ES2681420T3, HK1211466A1, HRP20181181T1, HUE039467T2, IL240246A, LT2950795T, MX367952B, PL2950795T3, PT2950795T, RS57469B1, SI2950795T1, WO2014121064A1 |
WO9912547A1 (Theramark Limited; 18 March 1999; United Kingdom; 8 September 2018) | Lapsed (A61K31/404, A61K31/407, A61K31/4155, A61K31/4174, A61K31/535, (IPC1-7): A61K31/40, A61K31/41, A61K31/415, A61K31/535) | AU9082698A, AU9082798A |
WO9912548A1 (Theramark Limited; 18 March 1999; United Kingdom; 8 September 2018) | ||
US2021220335A1 (IRP Health Pty Ltd.; 22 July 2021; Australia; 29 May 2039) | Under examination (A23K20/121, A23K20/137, A23K20/195, A23K50/30, A23L33/00, A23L33/10, A61K31/4164, A61K31/4375, A61K9/00, A61P31/04) | AU2019277198A1, CN112543635A, EP3810137A1, WO2019227149A1 |
WO2017072523A1 (University of Dundee; 4 May 2017; United Kingdom; 28 October 2036) | Lapsed (A61K31/454, A61P33/02) | None |
US10392363B2 (Neoculi Pty Ltd.; 27 August 2019; Australia; 28 August 2035) | Patented case (A61K31/155, A61K31/381, A61K31/404, A61K31/496, A61K31/505, A61K45/06, A61K9/00, C07C281/18, C07C335/40, C07D209/08, C07D239/50, C07D295/135, C07D333/58, A61K31/17, A61K31/341, A61K31/4045, A61K31/4192, A61K31/44, A61K31/498, C07C211/29, C07C251/24, C07C47/565, C07D209/14, C07D239/48, C07D241/20, C07D249/14, C07D251/54, C07D307/56, C07D311/58, C07D401/14) | AU2015311598A1, AU2020204441B2, BR112017004153A2, CA2959440A1, CN107106524B, EP3188722B1, JP2017528518A, RU2719593C2, RU2020113652A, US10829468B2, US2021009552A1, WO2016033635A1 |
US10562880B2 (Neoculi Pty Ltd.; 18 February 2020; Australia; 28 August 2035) | ||
US10752606B2 (Neoculi Pty Ltd.; 25 August 2020; Australia; 28 August 2035) | ||
WO2019244049A1 (Novartis; 26 December 2019; USA; 18 June 2039) | National phase entry in many countries (A61K31/4196, A61K31/4439, A61P33/02, C07D401/14, C07D403/06) | AU2019291490A1, BR112020025538A2, CA3100954A1, CL2020003252A1, CN112313217A, CR20200619A, CU20200102A7, EA202190064A1, ECSP20080991A, EP3810598A1, JOP20200327A1, JP2021528397A, KR20210022646A, MA52977A, PE20210780A1, PH12020552186A1, SG11202012628XA |
WO2019043701A1 (Bar-Ilan University; 7 March 2019; USA; 28 August 2038) | Entered into Europe (A61K31/155, A61K31/7105, A61K33/26, A61K38/00, A61K9/14, B82Y5/00, C01G49/02, C12N15/113) | EP3675875A1 |
US2021322329A1 (Gador Limitada; 21 October 2021; Chile; 21 August 2038) | Under examination (A61K31/541, A61K9/51, A61P33/02) | CA3113862A1, EP3842029A1, WO2020037438A1 |
US2021052498A1 (Northwestern University; 25 February 2021; USA; 29 July 2040) | Under examination (A61K31/4168, A61K47/34, A61K9/107, A61K9/127, A61P33/02) | None |
WO2021123775A2 (JPV01 Ltd.; 24 June 2021; United Kingdom; 16 December 2040) | No national phase entry (C07K14/705, C07K16/28) | None |
US9016221B2 (University of Florida Research Foundation; 28 April 2015; USA; 24 November 2025) | Patented case (A41D31/00, A61F2/02, A61L2/02, A61L27/00, B08B17/02, B08B17/06, B63B59/04, B64D15/00, A61F2/00, A61F2/12, A61F2/24, B63B1/36 | None |
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Imran, M.; Khan, S.A.; Alshammari, M.K.; Alqahtani, A.M.; Alanazi, T.A.; Kamal, M.; Jawaid, T.; Ghoneim, M.M.; Alshehri, S.; Shakeel, F. Discovery, Development, Inventions and Patent Review of Fexinidazole: The First All-Oral Therapy for Human African Trypanosomiasis. Pharmaceuticals 2022, 15, 128. https://doi.org/10.3390/ph15020128
Imran M, Khan SA, Alshammari MK, Alqahtani AM, Alanazi TA, Kamal M, Jawaid T, Ghoneim MM, Alshehri S, Shakeel F. Discovery, Development, Inventions and Patent Review of Fexinidazole: The First All-Oral Therapy for Human African Trypanosomiasis. Pharmaceuticals. 2022; 15(2):128. https://doi.org/10.3390/ph15020128
Chicago/Turabian StyleImran, Mohd, Shah Alam Khan, Mohammed Kanan Alshammari, Ashwaq Muiedh Alqahtani, Turkiah Abdullah Alanazi, Mehnaz Kamal, Talha Jawaid, Mohammed M. Ghoneim, Sultan Alshehri, and Faiyaz Shakeel. 2022. "Discovery, Development, Inventions and Patent Review of Fexinidazole: The First All-Oral Therapy for Human African Trypanosomiasis" Pharmaceuticals 15, no. 2: 128. https://doi.org/10.3390/ph15020128