First new chemical entity developed by DNDi and the first all-oral cure for both stages of 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 significant 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.

Fexinidazole is the first new chemical entity developed by DNDi, which has steered its progression 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 partnered with Sanofi from 2009 onwards for the development, manufacturing, and distribution of fexinidazole. Phase I studies started in 2009, and a Phase II/III clinical trial began in the Democratic Republic of Congo and the Central African Republic in 2012.

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 high 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 List 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. In 2020, DNDi and Sanofi also started the process to register fexinidazole with the US Federal Drug Administration.

Fexinidazole is now being donated by Sanofi to WHO for distribution to national sleeping sickness control programmes in disease-endemic countries. Distribution in the Democratic Republic of Congo began in January 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 Phase IIIb trial 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.

Treatment regimens

  • Indication: Stage 1 and Stage 2 T.b. gambiense sleeping sickness (human African trypanosomiasis)
  • Dosage: Adults: 3 tablets once-a-day for 4 days, and 2 tablets once-a-day for the next 6 days; Children (≥ 6 years old & ≥ 20 kg): 2 tablets once-a-day for 4 days, and 1 tablet once-a-day for the next 6 days 

Impact

  • Recommended in November 2018 by the European Medicines Agency under Article 58, an innovative regulatory mechanism for the review of new medicines destined for use outside of the European Union 
  • Registered in the Democratic Republic of Congo in 2018 
  • Approved by the US Food and Drug Administration (FDA) in July 2021.
  • Submission in other endemic countries underway 
  • Sanofi has committed to donate 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 the World Health Organization’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

Project updates

2020

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.

2019

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.

2018

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.

2017

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.

2016

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.

2015

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.

Key scientific articles

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, June 2021.
by Kande Betu Ku Mesu V, Mutombo Kalonji W, Bardonneau C, Valverde Mordt O, Ngolo Tete D, Blesson S, Simon F, Delhomme S, Bernhard S, Mahenzi Mbembo H, Mpia Moke C, Lumeya Vuvu S, Mudji E’kitiak J, Akwaso Masa F, Mukendi Ilunga M, Mpoyi Muamba Nzambi D, Mayala Malu T, Kapongo Tshilumbwa S, Botalema Bolengi F, Nkieri Matsho M, Lumbala C, Scherrer B, Strub-Wourgaft N, Tarral A.

Oral fexinidazole for late-stage African Trypanosoma brucei gambiense trypanosomiasis: a pivotal multicentre, randomised, non-inferiority trial. The Lancet, November 2017
by Kande Betu Ku Mesu V, Mutombo Kalonji W, Bardonneau C, Valverde Mordt O, Blesson S, Simon F, Delhomme S, Bernhard S, Kuziena W, Fina Lubaki JP, Lumeya Vuvu S, Nganzobo Ngima P, Mahenzi Mbembo H, Ilunga M, Kasongo Bonama A, Amici Heradi J, Lumaliza Solomo JL, Mandula G, Kaninda Badibabi L, Regongbenga Dama F, Kavunga Lukula P, Ngolo Tete D, Lumbala C, Scherrer B, Strub-Wourgaft N, Tarral A.

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, February 2014
by Tarral A, Blesson S, Valverde Mordt O, Torreele E, Sassella D, Bray MA, Hovsepian L, Evène E, Gualano V, Felices M, Strub-Wourgaft N.

Genotoxicity profile of fexinidazole – a drug candidate in clinical development for human African trypanomiasis (sleeping sickness). Mutagenesis, September 2012
by Tweats D, Bourdin Trunz B, Torreele E.

Antitrypanosomal activity of fexinidazole, a new oral nitroimidazole drug candidate for treatment of sleeping sickness. Antimicrob Agents Chemother, December 2011
by Kaiser M, Bray MA, Cal M, Bourdin Trunz B, Torreele E, and Brun R.

Fexinidazole – A new oral nitroimidazole drug candidate entering clinical development for the treatment of sleeping sickness. PLOS Neglected Tropical Diseases, December 2010
by Torreele E, Bourdin Trunz B, Tweats D, Kaiser M, Brun R, Mazué G, Bray M A, Pécoul B.

News and press releases

Documents

*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.).