The Expert Committee recommended the listing of fexinidazole on the core list
of the EML and EMLc for treatment of human African trypanosomiasis due to
Trypanosoma brucei gambiense infection.
The Committee noted that fexinidazole was demonstrated in clinical
trials to have success rates within acceptable margins compared to NECT, and
acceptable safety. The Committee acknowledged that as an orally administered
treatment, use of fexinidazole may offer both patient and health system advantages
compared to parenteral administration of other medicines for this disease.
The Committee noted that fexinidazole would be provided free of charge
through the WHO NTD department to national sleeping sickness control
programmes and treatment centres, and could contribute to the goal of disease
eradication, particularly in areas where access to health facilities is limited.
The application requested listing of fexinidazole on the core list of the EML and
EMLc for treatment of human African trypanosomiasis due to Trypanosoma
brucei gambiense infection.
Fexinidazole had not previously been considered for inclusion on the Model Lists.
The Model Lists currently include pentamidine and suramin sodium for
treatment of 1st stage African trypanosomiasis and eflornithine, melarsoprol and
nifurtimox for treatment of 2nd stage African trypanosomiasis (1).
Public health relevance
Human African trypanosomiasis (HAT), or sleeping sickness, is one of the most
neglected tropical diseases (NTDs). Without diagnosis and treatment, HAT is
usually fatal as the parasites multiply in the body, cross the blood–brain barrier
and invade the central nervous system at the late stage of the disease.
Human African trypanosomiasis takes two forms, depending on the
parasite involved: Trypanosoma brucei gambiense HAT and Trypanosoma brucei
rhodesiense HAT. T. b. rhodesiense causes an acute, rapidly progressive and fatal
disease and is present in 3% of HAT cases. T. b. gambiense is responsible for 97%
of HAT cases (2) and evolves to a fatal outcome between two and three years
after infection (3).
As of October 2012, 7106 annual cases of T. b. gambiense HAT had been
reported worldwide. With the increased efforts of control programmes and
availability of combination therapy with eflornithine and nifurtimox (NECT)
therapy, only 1420 gambiense HAT cases worldwide were reported to WHO
in 2017, the lowest level since the start of the systematic global data collection
75 years ago (4). However, the incidence is suspected to be under reported due to
different elements. The Democratic Republic of Congo (DRC) bears the majority
of disease burden (83–84% of the reported cases in 2012, 2015 and 2016 (4).
In view of the success in control of the disease, T. b. gambiense was
included in the WHO ‘roadmap’ for elimination and control of neglected tropical
diseases. A target date was set for global elimination of HAT as a public health
problem (<1 case/10 000 inhabitants in at least 90% of endemic areas) by 2020
with complete interruption of transmission in Africa targeted for 2030 (5).
Evidence of efficacy is based on data from three (yet to be published) clinical
efficacy and safety studies (DNDiFEX004, DNDiFEX005, and DNDiFEX006),
using data from 749 patients with HAT (from study sites in DRC and Central
African Republic), 619 of which were treated with fexinidazole. FEX006 included
125 paediatric patients aged between 6 and 15 years weighing 20 kg or more.
FEX004 compared fexinidazole and NECT in 394 adult patients (aged
≥15 years) with late stage 2 HAT. The success rate was 91.2% for fexinidazole
and 97.6% for the NECT combination. The primary objective of the study was
met. Fexinidazole was considered an acceptable treatment as the difference in
response compared to NECT was <13% in favour of NECT at 18 months after
the end of treatment (EOT). In the primary analysis, the difference in success rate
between groups remained within the margin of acceptable difference (−6.4%,
97.06% CI −11.2% to −1.6%). However, in the sub-population of patients with
cerebrospinal fluid white blood cell count (CSF-WBC) >100 /μL the efficacy was
86.9% in the fexinidazole arm versus 98.7%% in the NECT arm, and therefore
the risk of failure was higher in this sub-group with fexinidazole. The follow-up
analysis of the success rate at 24 months on the complete population (n=389)
yielded similar findings to those with partial data for 24 months at the primary
analysis timepoint (n=345) with only two new failures (one in each group).
FEX005 was an open-label single-arm cohort study of efficacy and
safety of fexinidazole in 230 adult patients with stage 1 or early stage 2 HAT. The
success rate with fexinidazole at 12 months after the EOT (98.7%; 95%CI 96.2%
to 99.7%), was greater than an unacceptable rate of 80%. No difference was seen
in efficacy at 12 months according to the stage of the disease. The success rate at
18 months improved slightly between the initial and follow-up analysis due to the
inclusion of the additional 69 patients in the follow-up analysis (all successes):
97.8% (95%CI 95.0 to 99.3) vs 96.9% (95%CI 92.9 to 99.0) in the initial analysis.
FEX006 was an open-label single-arm prospective study of efficacy and
safety of fexinidazole in 125 children aged ≥6 years and <15 years weighing
over 20 kg with any stage HAT. The success rate with fexinidazole at 12 months
after the EOT (97.6%; 95%CI 93.1% to 99.5%) was greater than an unacceptable
rate of 80% and compatible with a target rate of 92%. The success rate at 18
months improved slightly between the initial and follow-up analysis due to the
inclusion of the additional 40 patients in the follow-up analysis (all successes):
98.4% (95%CI 94.3 to 99.8), vs 97.6% (95%CI 91.8% to 99.7%) in the initial
Pooled analyses of data from FEX004, FEX005 and FEX006, revealed findings
consistent with observations from the individual study analyses, with regard
to the incidence of treatment emergent adverse events (TEAEs), TEAEs that
occurred between baseline and end of hospitalization (EOH), TEAEs that
occurred after EOH, and TEAEs that were considered by the Investigator as
possibly related to treatment. A total of 577 of 619 (93%) patients experienced
TEAEs. Overall, 506 of 619 (82%) patients reported a total of 2026 possibly
related TEAEs between initiation of treatment and EOT, with most being mild
or moderate. In study FEX004 in patients with late stage 2 disease, the overall
incidence of TEAEs was comparable between treatment groups (93.6% with
fexinidazole vs 92.3% with NECT).
The most commonly reported TEAEs across all fexinidazole-treated
patients (≥10% of patients) were vomiting (42%), headache (37%), nausea
(35%), asthenia (27%), insomnia (23%), tremor (22%), decreased appetite (20%),
dizziness (19%), dyspepsia (14%) and feeling hot (10%).
Comparing overall TEAEs between fexinidazole and NECT in late
stage 2 patients, there were notable differences between treatment groups;
these included higher rates in the NECT arm of pyrexia, chills, hyperkalaemia,
convulsions and procedural pain; and higher rates in the fexinidazole arm of
insomnia, tremor, headache, asthenia, nausea, dizziness, hypocalcaemia, feeling
hot, hypoalbuminaemia, abdominal pain (upper), chest pain and dyspepsia.
Vomiting was reported in a similar percentage of patients. All other TEAEs
occurred with similar frequency with NECT and fexinidazole in late stage 2
HAT patients, suggesting that the AEs were related to the underlying disease
or that both treatments were associated with increased risk of the events to
With regard to risk of QT prolongation, fexinidazole has been associated
with QTcF interval increases and its use is contraindicated in patients at risk of
QT prolongation, uncorrected electrolyte abnormalities, symptomatic cardiac
arrhythmia, clinically relevant bradycardia, severe congestive cardiac failure or
family history of sudden death.
Central nervous system/psychiatric events as well as emesis/vomiting
were observed with fexinidazole treatment. Asymptomatic reversible neutropenia
and elevated liver enzymes that were found at different dose regimens in Chagas
disease patients were not reported in HAT patients with the treatment regimen
used in the HAT studies.
Cost / cost effectiveness
Drugs for HAT are provided free of charge to the WHO via a public–private
partnership between WHO/Sanofi (pentamidine, melarsoprol and eflornithine)
and WHO/Bayer AG (suramin, nifurtimox).
Under a signed agreement between Sanofi and WHO, drugs are
donated to WHO, to be used exclusively for the treatment of HAT. Requests for
supplies are made to WHO by governments of disease-endemic countries and
organizations working in association with these governments. Stock control and
shipment of the drugs are undertaken by Médecins sans Frontières-Logistique
according to the agreement. Transport costs to countries are paid by Sanofi
through its partnership with WHO.
Similar to NECT and other HAT drugs, fexinidazole will be distributed
free of charge through the WHO Neglected Tropical Diseases Department to
national sleeping sickness control programmes (NSSCPs) and from there to
treatment centres. The product will not be available through wide logistics of
pharmacies or out of the predefined distribution system. No return on investment
With NECT, indirect costs including transport to hospital, food and
hospitalization costs are born by the patients. They should be significantly
reduced with fexinidazole when patients are not hospitalized and can be treated
close to their home.
Fexinidazole received a positive opinion by the European Medicines Agency
(EMA) under Article 58 on 15 November 2018. It is not yet included in the WHO
guidelines or any other national guidelines. However, WHO sleeping sickness
treatment guidelines will be under revision in order to consider integration of
fexinidazole as part of the therapeutic options to treat gambiense HAT.
Fexinidazole is a new oral treatment for sleeping sickness disease and is not yet
An application for fexinidazole was submitted to European Medicines
Agency (EMA) through Article 58 of Regulation (EC) No 726/2004. Article 58
is a mechanism whereby the EMA may give a scientific opinion, in cooperation
with the WHO, for the evaluation of medicinal products intended to prevent
or treat diseases of major public interest and exclusively intended for markets
outside the European Community. A positive opinion from EMA was given on
15 November 2018 for the following indication:
“Fexinidazole Winthrop is indicated for the treatment of both the firststage
(haemo-lymphatic) and the second-stage (meningo-encephalitic) of human
African trypanosomiasis (HAT) due to Trypanosoma brucei gambiense in adults
and children ≥6 years old and weighing ≥20 kg. Fexinidazole should be used in
line with official recommendations”
However, lower efficacy of fexinidazole as compared to NECT has been
seen in a sub-group of patients. Patients with cerebrospinal fluid white blood
count (CSF-WBC) >100/μL should only be treated with fexinidazole if no other
adequate treatment (e.g. NECT) is available or tolerated.
Registrations in DRC and Uganda are also scheduled. Further registrations
in other endemic African countries are not planned due to the specific registration
regulatory picture for human African trypanosomiasis products and related
Since 2009, NECT has become the first-line therapy for stage 2 HAT due to T. b.
gambiense and has improved the prognosis of treated patients (6), replacing
monotherapy with eflornithine. NECT treatment requires a minimum health
infrastructure and personnel to administer two slow infusions every day for
seven days, on top of an oral treatment every 8 hours for 10 days, requiring
systematic hospitalization, as well as being resource consuming for skilled
health staff in the environment in which HAT patients live (remote, poor
areas with little health infrastructure). NECT is not recommended for early
stage disease, instead, patients are treated with pentamidine administered via
Second line-therapy for stage 2 HAT due to T. b. gambiense includes
melarsoprol, an organoarsenic compound, which is highly toxic and to which
resistance has developed (7). Intravenous injections of melarsoprol are painful
and can cause phlebitis. The drug has been administered by use of lengthy
and complicated dosing schedules, however, an abbreviated 10-day regimen of
melarsoprol has been developed.
The limitations associated with current HAT therapy include mandatory
hospitalization and need for equipment and skilled and trained health staff to
administer IV infusions and/or injections. The repeated infusions needed with
current HAT therapy are not only painful but increase the risk of infection for
The distribution of treatment to remote health facilities due to heavy
components (38 kg per box which includes four treatments comprising drugs,
solvents and equipment), is also a costly logistical challenge (8).
Fexinidazole is orally administered once daily with food for 10 days.
Recommended dosage regimens are according to body weight.
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(including the 20th WHO Model List of Essential Medicines and the 6th WHO Model List of
Essential Medicines for Children). Geneva: World Health Organization; 2017. (WHO Technical
Report Series, No. 1006). Available from https://apps.who.int/iris/bitstream/handle/10665/
259481/9789241210157-eng.pdf, accessed 30 October 2019.
2. Franco JR, Cecchi G, Priotto G, Paone M, Diarra A, Grout L et al. Monitoring the elimination of
human African trypanosomiasis: Update to 2014. PLoS Negl Trop Dis. 2017;11(5):e0005585.
3. Simarro PP, Diarra A, Ruiz Postigo JA, Franco JR, Jannin JG. The human African trypanosomiasis
control and surveillance programme of the World Health Organization 2000-2009: the way
forward. PLoS Negl Trop Dis. 2011;5(2):e1007.
4. Global Health Observatory data repository - Number of new reported cases (T.b. gambiense) -
Data by country [website]. Last updated 20 September 2016. Geneva: World Health Organization;
2016. (http://apps.who.int/gho/data/node.main.A1636, accessed 30 October 2019).
5. Control and surveillance of human African trypanosomiasis: report of a WHO Expert Committee
2013. WHO Technical Report Series, No. 984. Geneva: World Health Organization; 2013.
6. Simarro PP, Franco J, Diarra A, Postigo JA, Jannin J. Update on field use of the available drugs for
the chemotherapy of human African trypanosomiasis. Parasitology. 2012;139(7):842–6.
7. Bisser S, N’Siesi FX, Lejon V, Preux PM, Van Nieuwenhove S, Miaka Mia Bilenge C et al. Equivalence
trial of melarsoprol and nifurtimox monotherapy and combination therapy for the treatment of
second-stage Trypanosoma brucei gambiense sleeping sickness. J Infect Dis. 2007;195(3):322–9.
8. Simarro PP, Cecchi G, Franco JR, Paone M, Diarra A, Ruiz-Postigo JA, et al. Mapping the capacities
of fixed health facilities to cover people at risk of gambiense human African trypanosomiasis. Int
J Health Geogr. 2014;13:4.