The first all-oral treatment for Trypanosoma brucei gambiense human African trypanosomiasis (g-HAT) has been proven to be effective and safe, according to the results of clinical trials led by the Drugs for Neglected Diseases initiative (DNDi) and its partners, published today in The Lancet.
Transmitted by the bite of an infected tsetse fly, HAT (or sleeping sickness) is usually fatal without treatment. g-HAT accounts for 98% of recorded sleeping sickness cases.
Between 2012 and 2016, an open-label randomized pivotal Phase II/III clinical trial compared the efficacy and safety of the new treatment, fexinidazole, with today’s first-line treatment, nifurtimox-eflornithine combination therapy (NECT), in meningo-encephalitic (stage-2) g-HAT patients. 394 patients were recruited across 10 sites in the Democratic Republic of Congo (DRC) and Central African Republic. Treatment success rates of 91.2% were measured for fexinidazole, with 97.6% for NECT, 18 months after the end of treatment. The results show that fexinidazole is effective within a predetermined acceptability margin, set following a survey with practitioners, based on the significant advantages of having a first-line treatment that is oral. There were no major differences in safety.
“NECT is extremely effective in treating patients for sleeping sickness and has played a central role in reducing the global burden of this deadly disease to under 2,500 cases a year today. But it involves multiple injections and requires substantial hospital infrastructure which limit access to patients living in remote areas, and poses a heavy burden on the health system,” said Dr Victor Kandé, Neglected Tropical Diseases Expert Advisor, Ministry of Health of the DRC, principal investigator of the trial and lead author of the Lancet article. “An oral treatment would make a real difference as it would remove many barriers to treatment, not least the need for qualified medical and nursing staff to administer parenteral treatment.”
Until NECT was introduced by DNDi and partners, g-HAT was often treated with an arsenic derivative that killed 1 in 20 patients. NECT has replaced this treatment for g-HAT, but patients still need a lumbar puncture to determine which stage of the disease they have. Fexinidazole is effective for both stages of the disease, so will remove this need.
Two additional studies confirmed the efficacy of fexinidazole in haemo-lymphatic (stage-1) and early-stage-2 g-HAT patients (98.7%), and in children (97.6%), 12 months after the end of treatment. 230 adults were recruited as a part of the safety and efficacy trial in stage-1 and early-stage-2 patients, and 125 children for the paediatric trial. Overall, these additional studies did not reveal any new safety signals regarding the use of fexinidazole.
“Having an oral drug like fexinidazole as a future first-line treatment, with NECT as a second line, opens the way for a paradigm shift in how national programmes and the World Health Organization (WHO) can tackle the disease, as well as facilitating the integration of disease management in the health system,” said Dr Nathalie Strub-Wourgaft, DNDi Medical Director. “In due course, treatment could be administered at the primary healthcare level, removing the need for hospitalization, and potentially, for the first time, patients could even take their entire treatment at home.”
These results enable Sanofi, DNDi’s industrial partner on fexinidazole, to proceed with steps towards regulatory approval through the European Medicines Agency (EMA) Article 58 procedure (which allows the EMA to give opinions, in co-operation with WHO, for the evaluation of certain medicinal products for human use that are intended exclusively for markets outside of the European Union), with a view to ensuring patient access to fexinidazole in HAT-endemic countries.
“The history of sleeping sickness shows that the disease is prone to resurging when it seems under control,” said Dr Gautam Biswas, Director ad interim, WHO Department of Control of Neglected Tropical Diseases. “Fexinidazole could make an important contribution towards sustaining the elimination of sleeping sickness.”
The DRC national control programme (the Programme national de lutte contre la trypanosomiase humaine africaine, or PNLTHA) played a key role in the implementation of the studies.
“The development of fexinidazole over the past decade bears witness to the value of the alternative non-profit R&D model, and in the DNDi approach of forging strong partnerships involving WHO, disease-endemic country Ministries of Health and national control programmes, and the pharmaceutical industry,” said Dr Bernard Pécoul, DNDi Executive Director. “This accomplishment is far from DNDi’s alone, but is one shared with all our partners and donors.”
- James Arkinstall, DNDi (Europe) +41 79392 9823
- Ilan Moss, DNDi (US) +1 646 266 5216
About sleeping sickness
Sleeping sickness (also known as human African trypanosomiasis or HAT) is caused by two subspecies of parasite, both transmitted by the tsetse fly. Trypanosoma brucei gambiense, which causes g-HAT, accounts for 98% of reported sleeping sickness cases, and is endemic in 24 countries of West and Central Africa. The majority of HAT patients are reported in the Democratic Republic of Congo, where 84% of cases are reported, followed by the Central African Republic, Guinea and Chad.
Until recently, the best available treatment for sleeping sickness, eflornithine monotherapy, involved 56 intravenous infusions and14 days in hospital, and was so complex to distribute and use in resource-poor settings that clinicians often resorted to using melarsoprol, a highly toxic, arsenic-based drug that killed 5% of those treated with it. Clinical trials developed by Epicentre, Médecins Sans Frontières/Doctors without Borders (MSF) and DNDi confirmed the non-inferiority of NECT, a simpler and shorter regimen presenting considerable benefits for patients compared to eflornithine. NECT is today used to treat 100% of reported stage-2 g-HAT cases.
In the 1970s, Hoechst (now part of Sanofi) had initiated but did not pursue pre-clinical development of fexinidazole. In 2005, the compound was identified by DNDi as having activity against the sleeping sickness parasite. Pre-clinical studies began in 2007. In 2009, DNDi and Sanofi concluded a collaboration agreement for the development, manufacturing, and distribution of fexinidazole, with DNDi responsible for pre-clinical, clinical, and pharmaceutical development, and Sanofi responsible for industrial development, registration, production and distribution of the drug. Phase I studies began in 2010, and the Phase II/III pivotal clinical study in 2012.
DNDi’s fexinidazole programme is supported by grants from the Bill & Melinda Gates Foundation, the UK Department for International Development, the Dutch Ministry of Foreign Affairs, the German Federal Ministry of Education and Research, the German Development Agency, the French Development Agency, the French Ministry for Europe and Foreign Affairs, the Norwegian Agency for Development Cooperation, the Spanish Agency for International Development Cooperation, the Republic and Canton of Geneva, International Solidarity Service, Switzerland, the Swiss Agency for Development and Cooperation, Médecins Sans Frontières/Doctors without Borders, and other private foundations and individuals.
A not-for-profit research and development organization, DNDi works to deliver new treatments for neglected diseases, in particular human African trypanosomiasis, leishmaniasis, Chagas disease, filarial infections, mycetoma, paediatric HIV, and hepatitis C. NECT is one of the seven treatments delivered by DNDi since its inception in 2003. Fexinidazole is DNDi’s first new chemical entity to successfully complete Phase II/III trials.