R&D status November 2015: DNDi Sleeping Sickness programme

Human African trypanosomiasis (HAT), also known as ‘sleeping sickness’, is transmitted by the bite of a tsetse fly. While currently its prevalence is declining, 21 million people are still at risk across 36 Sub-Saharan Africa countries with most of the cases occurring in the Democratic Republic of Congo (89% of all cases in 2013).

DNDi’s current HAT portfolio includes:


Research
Research

 

Two projects in the research phase:

Two backup candidates (SCYX-1330682 and SCYX-1608210) from the oxaborole class have been identified and are currently on hold in pre-clinical development in case SCYX-7158 (see project in clinical development) is precluded from further clinical development.

Currently, two oral drug candidates that are both new chemical entities (NCEs) are in clinical development for HAT which, if successful, could become the first-ever oral-only treatments for the disease:

Clinical development

Two oral drug candidates, both new chemical entities (NCEs), continue to progress through clinical development for HAT. If successful, they could become the first-ever oral-only treatments to be used for both stage 1 and stage 2 sleeping sickness, thereby replacing the complicated diagnosis and treatment paradigm, which includes systematic lumbar punctures of every diagnosed patient to determine the stage of the disease before deciding which treatment to administer.

Translation
Translation

One project in the translation phase:

 

  • SCYX-7158: The Phase I study with SCYX-7158, the first clinical candidate issued from the oxaborole class provided by Anacor Pharmaceuticals and developed in partnership with SCYNEXIS and others, was conducted and completed this year in France. It assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of SCYX-7158 after single oral ascending doses in 128 healthy human volunteers of sub-Saharan origin. It allowed for the therapeutic dose to be determined at 960 mg administered once as three tablets, with a favourable safety profile. As the drug has a long half-life (400 hours), the study was extended to ensure extensive safety monitoring of the healthy volunteers up to 210 days. This pharmacological finding has the advantage of translating into prolonged exposure with just one dose. These Phase I results confirm that the drug penetrates the brain, which is crucial to treat the late stage of the disease, where the parasite crosses the blood-brain barrier and kills patients if no treatment is given. Based on the results of this study, presented at the 9th European Congress on Tropical Medicine and International Health (ECTMIH) in September 2015, DNDi and partners plan to proceed to pivotal Phase IIb/III studies in 2016 at five sites in the Democratic Republic of the Congo (DRC), where 90% of cases occur. The sites (Bolobo, Kwamouth, Masimanimba, Isangi and Dipumba) are currently under preparation for inclusion of the first patients in 2016.

 

Development
Development

 

One project in the development phase:

 

  • Fexinidazole: The pivotal Phase II/III study with fexinidazole – the first success of the extensive compound mining efforts pursued by DNDi – aimed to explore new and old nitroimidazole drug leads, 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.[2] 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 6 and 14 years, also initiated in 2014, has recruited 125 patients to date. A 10-day oral-only treatment, fexinidazole, if successful, will be able to be administered at the primary healthcare level, ideally allowing patients to take their treatments at home. Sanofi is DNDi’s industrial partner for this project.

Currently in preparation, with fexinidazole:

  • A Phase IIIb study to acquire data on special population groups not yet included in the previous trials, notably pregnant women, patients with poor nutritional status, or with chronic diseases, who are hospitalized. The study also aims to provide preliminary information about the treatment compliance and effectiveness in out-patient care.

 

Implementation
Implementation

 

Implementation and access

  • NECT has been included in the WHO Essential Medicines List since 2009 and on the Essential Medicines List for children since 2013. Since June 2014, NECT has become available in all endemic countries, which receive free supplies from WHO via drug donations by Sanofi and Bayer.

 

From its HAT disease-specific portfolio DNDi aims to:

  • develop and register fexinidazole as a new drug for the treatment of stage 2 HAT caused by T.b. gambiense, ideally also for stage 1 HAT and T.b. rhodesiense

 

For more information on the partners and donors involved in DNDi’s HAT programme, please click on each hyperlink that will refer you to each project.


[1] Less than one case per 10,000 inhabitants in at least 90% of endemic foci is expected.

[2] Patient inclusion in CAR was stopped due to insecurity and conflict in the country.