DNDI: Development of First All-Oral Cure for All Stages of Sleeping Sickness Brings Easy-to-Use Medicine to Those in Need

Product: Fexinidazole

Product Type: Drug

Disease: Sleeping sickness (human African trypanosomiasis)

Sleeping sickness occurs primarily in the poorest, most remote rural areas in Africa, affecting people who are arguably among the most neglected and most excluded from medical innovation. The disease is usually fatal without treatment. Transmitted by the bite of a tsetse fly, it causes neuropsychiatric symptoms, including aggression, psychosis, the debilitating disruption of sleep patterns that give the neglected disease its name and, finally, coma. While sleeping sickness is now on the cusp of elimination, history shows that it can surge again if control measures are withdrawn, as happened in the 1960s and 1970s.

Until 2009, the best treatment for sleeping sickness, eflornithine, was extremely complex to distribute and administer in regions affected by the disease. All too often, doctors would have no choice but to use melarsoprol, a highly toxic, arsenic-based drug that killed 1 in 20 patients.[i]

In 2009, results from DNDi clinical trials showed that a simpler and shorter nifurtimoxeflornithine combination therapy (NECT) was safe and effective to treat sleeping sickness. Despite the considerable improvements brought about by NECT, the challenge of making treatment accessible in remote rural areas remained acute. The treatment is cumbersome — difficult to ship, store, and administer — and patients needed to be hospitalized to receive intravenous infusions and undergo a lumbar puncture to determine the stage of the disease, since NECT is only indicated for stage-2 sleeping sickness.

DNDi’s long-term strategy for sleeping sickness has focused on the development of entirely new and innovative oral treatments with the power to dramatically simplify treatment and support global sustainable elimination efforts.

Through an extensive compound mining exercise, DNDi screened more than 700 compounds from 15 different sources in academia and industry, in collaboration with the Swiss Tropical & Public Health Institute. These efforts led to the rediscovery of fexinidazole, which had been developed but abandoned for strategic reasons by Hoechst (now Sanofi) in the 1980s. In 2009, DNDi and Sanofi partnered to develop fexinidazole for sleeping sickness, with DNDi responsible for preclinical, clinical, and pharmaceutical development, and Sanofi responsible for industrial development, registration, and production.

“This first-ever all oral treatment for sleeping sickness, Fexinidazole, radically improves patient care, unburdens health systems, and opens the path to sustainable elimination of this disease. Moreover, it demonstrates the capacity of PDPs to bring brand new chemical compounds from the laboratory bench all the way through to the patients’ bedside.”

—DR BERNARD PÉCOUL, EXECUTIVE DIRECTOR OF DNDI

After several years of preclinical and Phase I trials, DNDi began a Phase II/III pivotal clinical study in the Democratic Republic of Conga (DRC) and the Central African Republic (CAR) in 2012.

The HAT Platform, bringing 120 members from over 20 institutions and set up with DNDi’s support since 2005, played an important role in supporting the challenging conduct of clinical trials in remote and conflict areas, providing extensive training in diagnostic and treatment procedures, pharmacovigilance, Good Clinical Practice (GCP), and medical waste management. This coordination and repeated training were essential for the undertaking of the clinical trial in a difficult context.

Through screening activities to identify patients eligible for clinical trials, DNDi also contributed significantly to national disease control efforts—supporting mobile teams that screened over 1,780,000 people from 2016 to 2018. All patients diagnosed with sleeping sickness received treatment, either with the standard of care (NECT) or with fexinidazole as participants in clinical trials. These screening efforts contributed to a better understanding of sleeping sickness prevalence and helped pave the way forward for sustainable elimination.

For many of the clinics involved, the trials represented partners’ very first experience conducting a clinical trial. Close collaboration with national sleeping sickness control programs and the HAT Platform helped overcome the significant challenges to conducting clinical research in very remote settings in accordance with international ethical and scientific quality standards.

More than 200 researchers, monitors, and practitioners were trained in GCP, universal standard precautions, laboratory diagnosis, patient examination techniques, laboratory procedures, treatment algorithms, pharmacovigilance, and waste management.

The three fexinidazole clinical trials, which enrolled 749 patients at 10 clinical sites in DRC and CAR, demonstrated the high efficacy and safety of fexinidazole for treatment of both stages of the disease in both adults and children.

Fexinidazole is the first all-oral treatment for both stages of T.b. gambiense sleeping sickness, the most common form of the disease. Taken as simple pills for 10 days, fexinidazole presents significant advantages over NECT because it eliminates the need for systematic hospitalization, thus reducing the number of painful lumbar punctures, while strengthening the primary care systems’ ability to accelerate treatment.

i.https://www.sciencedirect.com/topics/neuroscience/melarsoprol citing Meyler’s Side Effects of Drugs: The International Encyclopedia of Adverse Drug Reactions and Interactions, Sixteenth Edition