Fexinidazole: A crucial new treatment for sleeping sickness

Human African trypanosomiasis, or sleeping sickness, is a life-threatening tropical disease which is endemic in parts of sub-Saharan and eastern Africa. The disease is transmitted by the bite of the tsetse fly, and previous attempts at treatment have encountered a multitude of logistical and medical obstacles. However, through a process of global collaboration between Sanofi, the World Health Organization (WHO), and the Drugs for Neglected Diseases initiative (DNDi), with support from others, a vital new oral drug has been developed: fexinidazole. We spoke to Professor Heinz Haenel, whose work over the past few decades has been instrumental in the drug’s development.

Fexinidazole has the truly remarkable potential to eradicate sleeping sickness within a decade. Its continued use will immeasurably benefit those living in predominantly rural parts of sub-Saharan and eastern Africa. Few people are as well-equipped to tell the fascinating story of its development, disappearance, rediscovery, and recent clinical approval as Professor Heinz Haenel. From encountering the compound in its preclinical stage decades ago, to undertaking archival research to bring fexinidazole back into the light, Professor Haenel has been closely involved in the success and approval of the drug. We spoke about its past, present, and vitally important future.

Could you tell us about your professional history, and how this led to your research into Human African Trypanosomiasis, or sleeping sickness?

I am a zoologist by training. During my study at the Goethe University in Frankfurt/Main, I spent a few summer vacations as a “working student” at the company Hoechst AG. In those days they had a big department for parasitology. I got exposed to animal models on chagas, sleeping sickness, malaria, leishmaniasis and chicken coccidiosis. When I was working with the sleeping sickness model in mice in 1979, I also worked with a compound in development – HOE293 (Fexinidazole) – which was in the preclinical stage for chagas and sleeping sickness. As I specialised later in parasitology, I never forgot these exciting models and the life cycle of those parasites which often switch between insects and mammals.

What is the epidemiology of sleeping sickness – how prevalent has it been, and how dangerous is the disease?

Human African sleeping sickness (HAT) was considered a few years ago by the WHO to be one of the 10 most life-threatening tropical diseases. 65 million people in Africa are at risk of exposure to this disease. It spreads over 36 countries with a strong “hotspot” in the Democratic Republic of the Congo (DRC). The first huge outbreak was after the war, 1914-1918, when the colonial activities were strong in the countries affected. The introduction of the insecticide DDT and other measurements like tsetse fly catching lead to a decline down to low numbers around 1962. The resistance of the tsetse fly against DDT and the independence of some of the countries led to a new steep increase of cases with a death toll of around 50,000 in 2000.

The disease is transmitted by the bite of a male or female tsetse fly. The flies get infected by feeding on sleeping sickness patients. By taking up their blood the organism Trypanosoma brucei gambiense (a protozoan) enters the fly and make its way up to the salivary glands to be ready to infect healthy humans with the next bite.

The disease has two stages: a milder early stage and a severe second stage leading to death if untreated. At the end, patients fall into a coma and die.

“If the right partners are brought together the best science for this neglected population could be brought to the patients.”

What were the many struggles involved in finding an effective and deliverable treatment for sleeping sickness?

I am working with Sanofi. This company has been created by many mergers and acquisitions starting in the 18th century. Some of these companies had strong colonial ties to African countries. They developed intravenous drugs for treating HAT. These drugs were melarsoprol, eflornithine and pentamidine. Those drugs must be kept in a constant cold chain (2-6 °C) and can only be administered as an infusion with sterile saline. The logistics of this type of treatment over two weeks is a nightmare in certain countries in central Africa. In addition, drugs like melarsoprol (an arsenic derivative) are very toxic. 5% of all treated patients die from this treatment purely due to side effects.

The patients must spend 14 days in the hospital under the previous intravenous treatment and cannot do field work to feed their families. This is an additional burden which is no longer a problem with the new tablet of fexinidazole. Patients can be treated where they live and can continue their daily duties during treatment (10 days).

Nevertheless, we (Aventis and later Sanofi) started to work with WHO in 2001 and screened patients in all affected countries and treated all detected patients with our drugs, or in recent years with a combination of our eflornithine and a drug from Bayer AG (nifurtimox) called NECT. This treatment was the gold standard until our oral fexinidazole was approved.

Could you summarise the trajectory of discoveries which led to the development of fexinidazole?

Between 1959 and 1979 the Hoechst AG had a large group of chemists who synthesised molecules with the goal of discovering active treatments for parasitological and specifically tropical diseases. Those molecules were then tested first in vitro against the parasites and in case of efficacy they moved into animal models. Those few compounds which were effective, not toxic, easy to formulate, orally available and relatively cost effective in the manufacturing could then move into the clinical phase in humans (phases I to III).

In 1980, the parasitological department of the Hoechst AG was closed and the development of the molecule fexinidazole was stopped at the pre-clinical stage.

I published a review article on this class of compounds (nitroimidazoles) in 2003 in a parasitological journal. This article was analyzed by DNDi in Geneva and they contacted me as the oral compound fexinidazole was mentioned in one line of text. We got together and I agreed to look for the old reports on fexinidazole which were generated between 1975 and 1980 by the Hoechst AG. The search for those paper-based documents in the archives took some time but was finally successful. We agreed to collect money from governments and private sponsors (like the Bill and Melinda Gates Foundation) and repeated the preclinical studies in vitro and in animal models in Switzerland. After positive data we went into Phase I studies with African volunteers in France. After a successful Phase I, DNDi conducted two pivotal phase III trials in the DRC and the Central African Republic.

Between 2012 and 2016, an open-label randomised Phase II/III clinical trial compared the efficacy and safety of oral fexinidazole, with today’s first-line treatment, i.v/oral nifurtimox-eflornithine (NECT), in meningo-encephalitic (stage-2) 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% (absence of Trypanosoma sp.) were measured for fexinidazole, with 97.6% for NECT, 18 months after the end of treatment.

Sanofi compiled a submission dossier which was submitted to the EMA under “article 58” (for use in countries outside the EU) in December 2017. A positive opinion was granted in November 2018 and one month later fexinidazole was approved in the DRC.

“Together with the WHO,
Sanofi has given a commitment to eradicate HAT by 2030.”

How important has global collaboration been in the process of developing fexinidazole?

The collaboration between DNDi, the WHO, Sanofi and the various sponsors was mandatory. No partner of this consortium could have done it alone. If the right partners are brought together the best science for this neglected population could be brought to the patients.

Do you think lessons were learnt during this process that could be readily transferable to the search for other global disease treatments?

Yes, definitely. I consider this as a “role model” for other neglected diseases. I am convinced that in the compound archives of other pharmaceutical companies and universities many hidden treasures are waiting for re- discovery.

Given this remarkable new treatment, how is the future looking for sleeping sickness?

Together with the WHO, Sanofi has given a commitment to eradicate HAT by 2030. With this new tablet which is easy to distribute and free of charge for the patients we can achieve this goal. Our biggest problem is the ongoing political uncertainty in DRC and the various changing rebel groups which are often a roadblock for smooth and plannable treatment schedules.

What future work are you hoping to undertake with Sanofi?

I will retire this August 2021, so there is not much time left for new projects. Currently, I am active in the development of new and patient friendly anti-diabetic drugs.

Contact
Heinz Haenel

E: [email protected]
T: +49 173 306 3481

Fexinidazole: A crucial new treatment for sleeping sickness