Fexinidazole: All-Oral Therapy for Human African Trypanosomiasis: Comparison
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Human African trypanosomiasis (HAT or ‘sleeping sickness’) 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. 

  • neglected disease
  • trypanosomiasis
  • fexinidazole
  • PATENT
  • DISCOVERY
  • DEVELOPMENT

1. Introduction

Neglected tropical diseases (NTDs) including human African trypanosomiasis (HAT or ‘sleeping sickness’), and Chagas disease (American trypanosomiasis) are a diverse set of illnesses that primarily afflict people of tropical and sub-tropical countries, which are linked to extreme poverty [1]. HAT is caused by the protozoan Trypanosoma brucei (T.b.), whereas Chagas disease is caused by Trypanosoma cruzi [1]. HAT is the major NTD in Africa and its presence has been recorded in about 37 countries, especially in sub-Saharan African countries [2].
HAT is a vector-borne disease, wherein the parasites (T.b. rhodesiense and T.b. gambiense) enter the human body through the bite of tsetse flies [3][4]. The HAT caused by T.b. gambiense (gHAT) (Western and Central African form) is a chronic form of the disease and is responsible for about 85–90% of cases of HAT. The signs and symptoms of gHAT appear after months or years. The HAT caused by T.b. rhodesiense (rHAT) (Eastern and Southern African form) is an acute form of the disease and is responsible for about 10–15% of cases [3][4][5]. The signs and symptoms of rHAT appear after 2–3 weeks. After the bite of the tsetse fly, the parasite enters the body and triggers two stages of the disease. In stage 1 (haemolymphatic stage), the parasite multiplies and spreads all over the bloodstream, systemic organs, and lymphatic system. The common non-specific symptoms of stage 1 are similar to those of the common cold, fever, headache, and joint pain [3][4]. In stage 2 (encephalitic stage) which starts after one year or later, the parasite enters the central nervous system (CNS). Stage 2 of HAT leads to chronic encephalopathy with brain damage, giving rise to neuropsychiatric disorders, poor concentration, disruption of the sleep–wake cycle, and prolonged states of drowsiness. Therefore, it is also called sleeping sickness. In the early phase of stage 2, the WBC count is slightly high in the cerebrospinal fluid (6–20 cells per µL of CSF) which subsequently increases sharply in the late phase of stage 2. The CNS infection ultimately leads to coma and the patient’s death [3][4]. The gHAT and rHAT can be diagnosed by direct visualization of the trypanosomes in blood or organ samples under a microscope, serological tests, card agglutination test, and the RDP rapid diagnostic test as SD bioline [3][4][5][6][7]. If untreated, HAT is always fatal and leads to death. The current treatment for HAT is provided in Table 1.
Table 1. Current treatment option for human African trypanosomiasis.
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 [8].
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 [9].
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 [10].
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
) which provide most if not all the trypanocidal activity against Trypanosomia brucei gambiense strains of the parasite. The sulfone metabolite (M2) does not seem to go through further metabolism [19][22][21][23]. The elimination of FEX is almost completely extra-renal, wherein the majority of the excreted metabolites are M1 and M2 [19][21]. The reported half-life (hours) of FEX, M1, and M2 are 15.0, 16.0, and 23.0 h, respectively [19][21], whereas the clearance (liter/hour) of FEX is 161.0 [19]. The adverse effects of FEX include QT prolongation, CNS and psychiatric-related adverse reactions, risk of infection, hepatotoxicity, and disulfiram-like reactions [19]. The toxic (overdose) effects of FEX in adults (3600 mg/day for 14 days) comprise elevated levels of transaminases, panic attack, and vomiting. The safety and efficacy of FEX for the treatment of both stages of HAT have been established in children ≥ 6 years old and weight ≥ 20 kg (National clinical trial numbers 02169557 and 02184689, Table 2). However, such pediatric patients may be more sensitive to vomiting. The safety and efficacy of FEX have not been established in children <6 years old and weight <20 kg [19]. The overdose in pediatric HAT patients causes elevated potassium, reduced calcium levels, and vomiting. The treatment of FEX toxicity is supportive therapy with monitoring due to the lack of its antidote [19][22]. The metabolism of FEX involves many enzymes including CYP1A2, CYP2B6, CYP2C19, CYP2D6, CYP3A4, CYP3A5, and flavin mono-oxygenase-3 (FMO-3). Therefore, drugs, including herbal medicines, which are metabolized by these enzymes may interfere with the FEX treatment [19].
Table 2. Interventional clinical trials on fexinidazole.
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)
[11].
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 [12].
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 [13].

It is evident from Table 1 that few treatments are available for HAT, wherein nifurtimox and pentamidine are USFDA approved drugs. Most of these treatments are injectable and are effective either for stage-1 or stage-2 of HAT [8][9][10][11][12][13]. None of the available treatments are effective in treating stage-1 as well as stage-2 of HAT. Most of the treatments require a skilled person for IV administration, which increases the financial burden on the patient.

2. Fexinidazole (FEX)

FEX (Figure 1), a 2-substituted-5-nitroimidazole antiprotozoal agent, chemically is 1-methyl-2-{[4-(methylthio)phenoxy]methyl}-5-nitro-1H-imidazole (molecular formula: C12H13N3O3S: molecular weight: 279.3; CAS registry number: 59729-37-2; Other identifiers: HOE-239) [13][14][15][16]. It is a yellow crystalline, non-hygroscopic powder, which is practically insoluble in water, sparingly soluble in acetone and acetonitrile, very slightly soluble in ethanol, and slightly soluble in methanol. It is an achiral molecule and does not have optically active isomers [13][14][15][16]. It is marketed as a base, and only one polymorphic form-I is identified to date. FEX exhibits solubility and permeability characteristics consistent with BCS class II drugs [17].
Pharmaceuticals 15 00128 sch001 550
Scheme 1. Development timeline for fexinidazole.

3. Pharmacology of FEX

The nitroheterocyclics require bio-activation of their nitro groups to become biologically active. The nitro-reductase (NTR) enzyme is shown to activate the nitroimidazoles FEX and nifurtimox in the parasites [18]. The NTR enzyme of the parasite activates FEX and its active metabolites (FEX sulfoxide and FEX sulfone) (Scheme 2) to generate reactive amines that damage the DNA and proteins of the parasite. However, the precise mechanism by which FEX, FEX sulfoxide, and FEX sulfone demonstrate action against T. brucei is still unknown [19]. One study has stated that the action of the NTR enzyme on nitroaromatic compounds (Nifurtimox and Benznidazole) leads to the generation of different toxic fragments (open chain nitrile and hydroxylamine) that exert their effects against T. brucei [20]. The chemical structure of Benznidazole is similar to FEX [20]. Therefore, the authors believe that there is a possibility that the NTR enzyme converts the nitro group of FEX to nitroso intermediate followed by the generation of hydroxylamine intermediate. The hydroxylamine intermediate may be responsible for the activity of FEX against T. brucei.
Pharmaceuticals 15 00128 sch002 550
Scheme 2. Transformation of fexinidazole into its metabolites.
FEX is well absorbed orally. After oral administration, FEX rapidly converts to its active metabolites, FEX sulfoxide (M1) and FEX sulfone (M2) (Scheme 2) [19][21]. FEX tablet must be swallowed (not chewed) during or just after a solid meal (not liquid meal) to increase its absorption (2–3 times), especially for stage-2 HAT. A dose administered without food is considered as a dose skipped [19]. The apparent volume of distribution of FEX is 3222 ± 1199 L [19], whereas the protein binding of FEX, M1, and M2 are 98%, 41%, and 57%, respectively [19][21]. FEX is rapidly metabolized via hepatocytes to the M1 and M2 metabolites (Scheme 2
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)
In clinical trials, a difference in the efficacy of FEX has been detected in both stages of HAT (National clinical trial number 01685827; Table 2). In the first stage of HAT, a treatment success rate of 98.7% and 97.6% was observed. However, a decrease in the efficacy of FEX (86.9%) was seen in a comparison of nifurtimox-eflornithine combination therapy (98.7%) in the second stage of HAT. Furthermore, all-cause mortality was higher in FEX treated patients (4.4%) than nifurtimox-eflornithine combination therapy (0%). Accordingly, the patients of the second stage of HAT can be treated with FEX in the absence of other treatment options like nifurtimox-eflornithine combination therapy [19]. The safety and efficacy of FEX have not been fully established in certain populations (children below 6 years, pregnant/lactating women, and hepato-compromised patients) [19].
It is evident from Table 2 data that the Drugs for Neglected Diseases initiative is developing FEX for the treatment of other neglected diseases also (Chagas disease, South American Trypanosomiasis, Leishmaniasis, and Trypanosomiasis). These clinical trials indicate the foreseeable potential of FEX to treat many neglected diseases, and make FEX an important molecule for neglected diseases.

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