Status: Fexinidazole, a drug candidate for stage 2 HAT, is the first success of the proactive compound mining efforts DNDi pursued in the Nitroimidazole Project. Fexinidazole was in pre-clinical development as a broad-spectrum antiprotozoal at Hoechst AG in the early 1980s, but was then abandoned. DNDi ’rediscovered’ it and an extensive profiling has shown that fexinidazole is orally active in animals, crosses to the brain in mice, and has cured in models for both acute and chronic infections with African trypanosomes. Additionally, fexinidazole is not mutagenic (i.e. is not capable of inducing mutation) in a panel of in vitro and in vivo mammalian genetic toxicology tests, confirming its favourable activity/toxicity profile as a drug candidate.

In 2007, a full pre-clinical programme was established to enable first-in-human studies. This included: process chemistry; GMP (good manufacturing practice) manufacturing of the active pharmaceutical ingredient; pre-clinical formulation; ADME-PK (absorption, distribution, metabolism, excretion, and pharmacokinetics) profiling and confirmatory studies in animal models of HAT; and the regulatory toxicology package. In May 2009, DNDi signed an agreement with sanofi-aventis (now: Sanofi), whereby DNDi is in charge of non-clinical, clinical, and pharmaceutical development, and Sanofi is responsible for the industrial development, registration, and production of the drug at its manufacturing sites. Fexinidazole entered into Phase I first-in-human studies in September 2009, making it the only new drug candidate in clinical development for sleeping sickness at that time. Since March 2012, Oxaborole SCYX-7158 also entered clinical study, making it the second new drug candidate in clinical development (for sleeping sickness as well).

In 2010, DNDi carried out two new Phase I studies assessing safety and pharmacokinetic profile after administration of fexinidazole with field-adapted food both in single and multiple doses. Together with DNDi’s partner Sanofi, parallel scientific advice from EMA (under the scope of the article 58) and FDA on the clinical development plan for fexinidazole took place in January 2011. The consultation resulted in the acceptance of a single pivotal Phase II/III study to prove the efficacy and safety of fexinidazole as a basis for submission for review by EMA. In 2011, the completion of the Phase 1 studies led to the choice of the therapeutic dose of a single daily dosing with food for 10 days: a loading dose of 1800mg / day for 4 days followed by a maintenance dose of 1200mg / day for 6 days.

In February 2012, an international ethical review of the protocols for DNDi and partners’ pivotal Phase II/III fexinidazole study was organized in Paris, France. Chaired by the Société Française et Francophone d’Ethique Médicale (SFFEM), the review brought together – for the first time ever – the Ethics Department of WHO and representatives of ethics committees from six African countries with the aim of reducing duplication of efforts.

Submission of the protocol and regulatory documentation to the local Ethics Committee and Regulatory Authorities is ongoing. Study sites have already been selected and prepared in the Democratic Republic of the Congo and in Central African Republic. The Phase II/III study will start mid-2012.