Develop and promote access to fexinidazole as a new all-oral treatment for Stage 1 and Stage 2 sleeping sickness caused by T.b. gambiense in adults and children above the age of six and over 20 kg
current phase of drug development
updated 16 Feb 2023
First new chemical entity developed by DNDi and the first all-oral cure for T.b. gambiense sleeping sickness
Easy-to-use medicine brings treatment closer to patients
Fexinidazole is the first all-oral treatment for both stages of T.b. gambiense sleeping sickness, the most common form of the disease. Fexinidazole is an oral pill taken for 10 days, offering practical advantages over the previous standard of care, NECT, because it eliminates the need for systematic hospitalization and leads to a reduction in the number of lumbar punctures. The European Medicines Agency adopted a positive scientific opinion on fexinidazole in late 2018, paving the way for registration and distribution in endemic countries. The drug was registered in the Democratic Republic of Congo in December 2018 and in Uganda in October 2021. Other endemic countries are using fexinidazole through special authorizations of their ministries of health.
Fexinidazole has progressed through all stages of the drug development pipeline from lab to patient. The search began in 2005, when DNDi, in collaboration with the Swiss Tropical and Public Health Institute, undertook an extensive compound mining exercise to search for anti-parasitic activity and rediscovered fexinidazole, whose development had been shelved by Hoechst AG (now Sanofi) in the 1980s. After completing preclinical studies, DNDi has partnered with Sanofi since 2009 to develop, manufacture, and distribute fexinidazole. Phase I studies started in 2009, and a pivotal Phase II/III clinical trial began in the Democratic Republic of Congo and the Central African Republic in 2012, followed by two other cohort studies targeting larger populations (early-stage patients and children).
More than two million people were screened for sleeping sickness as part of three fexinidazole clinical trials, which enrolled 749 patients in the Democratic Republic of Congo and Central African Republic and had to overcome unique challenges of conducting trials in remote areas where sleeping sickness occurs. In the trials, fexinidazole showed good efficacy and safety in both stages of the disease for adults and children.
In June 2019, fexinidazole was added to the World Health Organization (WHO) Essential Medicines Lists for children and adults. In August 2019, WHO published new sleeping sickness treatment guidelines to include fexinidazole as the first-line treatment for T.b. gambiense, except in cases of advanced disease, were NECT remains the preferred choice.
Fexinidazole is now being donated by Sanofi to WHO for distribution to national sleeping sickness control programmes in disease-endemic countries. The first patient to receive fexinidazole outside of clinical trials was treated in the Democratic Republic of Congo in March 2020.
DNDi is now striving to make fexinidazole available to the majority of people who have T.b. gambiense sleeping sickness. We are supporting a three-year access and pharmacovigilance study that began in 2020 and have so far carried out in-country training of relevant staff in 250 hospitals and health centres in T.b. gambiense-endemic countries; and updated national treatment and pharmacovigilance guidelines in Angola, Central African Republic, the Democratic Republic of Congo, Equatorial Guinea, Guinea, and Chad.
DNDi has successfully completed a further Phase IIIb trial in the DRC and Guinea to obtain clinical data on special populations not included in previous trials, including pregnant and breast-feeding women, and people with poor nutritional status or chronic diseases. The final report is being prepared.
- Indication: Stage 1 and Stage 2 T.b. gambiense sleeping sickness (human African trypanosomiasis)
- Dosage: Adults: 3x 600mg tablets once a day for 4 days, and 2x 600mg tablets once a day for the next 6 days; Children (≥ 6 years old & ≥ 20 kg): 2x 600mg tablets once a day for 4 days, and 1x 600mg tablet once a day for the next 6 days
- Recommended in November 2018 by the European Medicines Agency under the EU-M4All procedure (previously known as the Article 58 procedure), an innovative regulatory mechanism for the review of new medicines destined for use outside of the European Union
- Added to the WHO Essential Medicines List in 2019
- Approved by the US Food and Drug Administration in July 2021
- Registered in the Democratic Republic of Congo in 2018 and in Uganda in October 2021
- Approved for use by ministries of health in other endemic countries
- Submission in other endemic countries underway
- Sanofi donates fexinidazole to WHO, which will distribute it to National Control Programmes in endemic countries
- Developed in partnership between DNDi; Sanofi; the HAT Platform; national control programmes of the Democratic Republic of the Congo, Central African Republic, and Guinea; Médecins Sans Frontières; Swiss Tropical and Public Health Institute; with support from WHO’s Department of Control of Neglected Tropical Diseases
‘Those affected by sleeping sickness are some of the most vulnerable and live in some of the most remote areas of the Congo, if not the world. They need a treatment that is safe, effective and simple. An all-oral treatment has been a dream of mine for decades. Fexinidazole is a huge leap in how we can tackle this deadly disease.’
Dr Victor Kande, NTD Expert Advisor to the Ministry of Health of DRC and principal investigator of the fexinidazole clinical trials
The clinical development of fexinidazole for T.b. gambiense sleeping sickness was completed with the finalization of the last clinical study report, which is expected to be published in 2023. Access activities continued throughout the year, including in additional countries where fexinidazole has been adopted as the first-line treatment for sleeping sickness caused by T.b. gambiense. The post-approval safety study will be finalized in the second quarter of 2023. Training on the new treatment guidelines was completed and the team is now concentrating on improving routine pharmacovigilance reporting using fexinidazole as an example in five countries (Democratic Republic of the Congo, Central African Republic, Guinea, Angola, and South Sudan). The ethnographic study was completed and published.
In July 2021, DNDi and Sanofi registered fexinidazole with the US Federal Drug Administration, obtaining the rights for a priority review voucher. Access activities launched in 2020 continued and will run until at least 2024. These activities include extending diagnosis and treatment coverage in the health system through the rehabilitation, construction, and equipping of health centres and training of health staff; supporting safety follow-up within the Sanofi post-approval safety study; reinforcing national pharmacovigilance systems in five of the most endemic countries to guarantee sustainable safety reporting; and conducting ethnographic research to inform and reinforce community awareness and develop new communication tools and campaigns.
Fexinidazole distribution began in January 2020 in the Democratic Republic of Congo. DNDi continued to support the roll-out of fexinidazole, including active support for access and pharmacovigilance activities, in Angola, Central African Republic, the Democratic Republic of Congo, Guinea, and South Sudan. In September 2020, DNDi received funding through the Democratic Republic of Congo’s Health System Strengthening for Better Maternal and Child Health Results (PDSS) project to continue in-country training, in collaboration with the HAT Platform, for relevant staff from 250 hospitals and health centres in countries where T.b. gambiense is endemic.
Patient follow-up for DNDi’s Phase IIIb trial to obtain clinical data on special populations concluded in February 2021; however, the COVID-19 pandemic caused monitoring visits in Guinea to be put on hold. Study results are expected in late 2021.
Fexinidazole is now being donated by Sanofi to the World Health Organization (WHO) for distribution to national sleeping sickness control programmes in HAT-endemic countries. Fexinidazole distribution began in January 2020 in DRC. DNDi is supporting roll-out of fexinidazole and pharmacovigilance activities in DRC, Guinea, Central African Republic, Angola, and South Sudan to scale up access to this oral treatment for sleeping sickness caused by T.b. gambiense.
WHO began training of trainers in 2019, first in DRC, followed by trainings in the HAT-endemic countries of Central and West Africa. DNDi will continue in-country training in collaboration with the HAT Platform, targeting relevant staff from 250 hospitals and health centres in T.b. gambiense-endemic countries.
The last patients in the Phase IIIb trial whose purpose was to obtain additional clinical data on special populations (including pregnant and lactating women, and patients with poor nutritional status or chronic diseases) completed enrolment in August 2019. Post-treatment follow-up is anticipated to be completed by the end of 2020. A Phase IV access and pharmacovigilance project will begin in 2020.
Fexinidazole received a positive scientific opinion by the the European Medicines Agency’s Committee for Medicinal Products for Human Use in November 2018 and was registered in the Democratic Republic of Congo in December 2018.
A Phase IIIb trial that started in 2016 is still ongoing, with 116 patients (of a target 174) recruited. Patients are treated either in hospital, or at home, thereby also providing preliminary information about treatment adherence and final effectiveness in ambulatory patients. In 2018, two new clinical sites in DRC (Nkara and Kimpese) and one in Guinea (Dubreka) were added to the already active sites.
In addition, a Phase IV study to support access to fexinidazole and collect pharmacovigilance data is also under preparation. The first patients are expected to be enrolled by the end of 2019.
Lastly, a Phase II/III study is being prepared in Malawi to assess fexinidazole to treat HAT caused by T.b rhodesiense, the other subspecies of the parasite that causes sleeping sickness, and one that causes a more virulent strain of the disease occurring primarily in East and Southern Africa. Protocols have been submitted and the study should start in mid-2019.
Phase II/III study results published in 2017 confirmed that fexinidazole is safe and effective, and presents significant advantages over NECT, as it removes both the need for a systematic lumbar puncture and patient hospitalization. A regulatory dossier was submitted to the European Medicines Agency under Article 58 for the treatment of T.b. gambiense HAT (stages 1 and 2). Results were presented at ECTMIH in October 2017 and published in The Lancet.
The Phase IIIb trial that started in 2016 to obtain more information about special populations not included in previous fexinidazole trials is ongoing. Recruitment continued in 2017 with the inclusion of 45 patients (out of 174 in total) in five sites (Bandundu, Bagata, and Mushie, Masi Manimba, and Dipumba). Three more sites are planned to be opened in 2018, including one in Guinea.
Two additional complementary cohorts with fexinidazole were completed in 2016, one including 230 adult patients with stage 1 and early stage 2 of the disease, and another including 125 children between 6 and 14 years, both in DRC sites. Follow up of patients will be completed in 2017.
A Phase IIIb aiming at getting more information about special population groups not included in previous fexinidazole trials (including pregnant or lactating women, and patients with poor nutritional status or with chronic diseases) started in 2016. Patients will be treated either in hospital, or at home, thereby providing also preliminary information about the treatment compliance and final effectiveness in ambulatory patients. Three sites were initiated (Bandudu, Mushie and Bagata) and six patients (out of a target of 174) had been recruited by the end of 2016.
The results of the Phase II/III study support the submission of a regulatory dossier to the European Medicines Agency under Article 58, planned for late 2017 for the treatment of g-HAT with fexinidazole. It aims to facilitate faster WHO prequalification of the medicine as well as regulatory approvals and implementation in endemic countries. A risk management plan to further monitor safety and efficacy in the field is under preparation in collaboration with Sanofi and WHO.
In addition, the protocol for a study to be undertaken in r-HAT patients is being finalized, sites in Uganda and Malawi have been identified.
The pivotal Phase II/III study with fexinidazole completed this year, the recruitment of 394 stage 2 HAT patients at ten clinical sites in the Democratic Republic of Congo and the Central African Republic. A second study in adult patients with stage 1 and early stage 2 of the disease that was initiated in 2014 has recruited 228 patients to date. A third study in children between six and 14 years, also initiated in 2014, has recruited 125 patients to date.
News & resources
- 22 February 2023 - HAT Platform Newsletter No. 22
- 27 September 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
- 19 July 2021 - US FDA approves fexinidazole as the first all-oral treatment for sleeping sickness
- 16 June 2021 - Oral fexinidazole for stage 1 or early stage 2 African Trypanosoma brucei gambiense trypanosomiasis: A prospective, multicentre, open-label, cohort study, The Lancet Global Health
- 1 February 2021 - Palmarès Prescrire 2020 des médicaments : trois médicaments primés, Prescrire
- 17 June 2020 - Ending the neglect of sleeping sickness
- 10 July 2019 - WHO adds first all-oral sleeping sickness drug to Essential Medicines List
- 30 January 2019 - Fexinidazole, the first all-oral treatment for sleeping sickness, approved in Democratic Republic of Congo
- 16 November 2018 - A doctor’s dream: A pill for sleeping sickness
- 16 November 2018 - A doctor’s dream
- 16 November 2018 - European Medicines Agency recommends fexinidazole, the first all-oral treatment for sleeping sickness
- 31 January 2018 - Sanofi and partner seek European Medicines Agency review for sleep sickness product, Reuters
- 9 November 2017 - Oral fexinidazole for late-stage African Trypanosoma brucei gambiense trypanosomiasis: A pivotal multicentre, randomized, non-inferiority trial, The Lancet
- 4 November 2017 - Phase II/III studies show high efficacy and safety of fexinidazole, the first oral treatment for sleeping sickness
- 25 February 2014 - Determination of an Optimal Dosing Regimen for Fexinidazole, a Novel Oral Drug for the Treatment of Human African Trypanosomiasis: First-in-Human Studies, Clinical Pharmacokinetics
- 6 December 2012 - New Oral Drug Candidate for African Sleeping Sickness
- 23 August 2012 - Genotoxicity profile of fexinidazole – a drug candidate in clinical development for human African trypanomiasis (sleeping sickness), Mutagenesis
- 18 December 2011 - Antitrypanosomal activity of fexinidazole, a new oral nitroimidazole drug candidate for treatment of sleeping sickness, Antimicrob Agents Chemother
- 20 December 2010 - Fexinidazole – A new oral nitroimidazole drug candidate entering clinical development for the treatment of sleeping sickness, PLoS Negl Trop Dis
- 18 May 2009 - Sanofi-aventis and DNDi enter into a Collaboration Agreement on a New Drug for Sleeping Sickness, Fexinidazole
Social science study
An ethnographic study exploring the perceptions and practices of local communities regarding sleeping sickness was conducted in the Democratic Republic of Congo to improve the access to health services.
Read the report [in French]: Rapport de l’étude ethnographique « Des perceptions et pratiques des communautés locales en rapport avec la maladie du sommeil dans 14 zones de santé endémique en République Démocratique du Congo »
- Clinical study protocol: DNDiFEX004
- Clinical study protocol: DNDiHATFEX005
- Clinical study protocol: DNDiHATFEX006
*From 2005 to 2018, DNDi invested EUR 55 million for the full development of fexinidazole from discovery to clinical trials development (except the Phase IIIb trial that started in 2016 to obtain more information about special populations not included in previous fexinidazole trials). Project cost includes direct and indirect costs, but it does not include in-kind contributions. As of December 2018, Sanofi estimates an overall contribution of EUR 13 million (including regulatory, human resources, industrial activities, etc.).
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