Acoziborole: drug can put sleeping sickness to bed

During the last epidemic, the prevalence reached 50% in several villages in Angola, the Democratic Republic of Congo and South Sudan. Sleeping sickness was the first or second leading cause of mortality in these communities, even ahead of HIV/AIDS

About 10 thousand new cases of human African human trypanosomiasis (HAT), better known as sleeping sickness, are reported each year. However, it is estimated that many cases go undiagnosed. Screening the population at risk is a major investment, both in terms of the number of people needed to perform them and in terms of materials, which are often in short supply in the areas of Africa where trypanosomiasis is found. Some 65 million people in sub-Saharan Africa are at moderate to very high risk of being infected. For decades, the only available treatment was melarsoprol, an arsenic derivative that killed 1 in 20 patients. The disease can be fatal if left untreated.

In 2012, a study led by the Drugs for Neglected Diseases Initiative (DNDi) allowed the development of the drug fexinidazole, completely oral and without serious side effects. Its use was approved in November 2018, representing a new era in the treatment of sleeping sickness. In 2021, the USA National Food and Drug Administration (FDA) approved fexinidazole as the first completely oral treatment for two-stage sleeping sickness. It is indicated for sleeping sickness caused by Trypanosoma brucei gambiense (g-HAT), the most common form of the disease in western and central Africa, as a once-daily treatment for 10 days.

An easily accessible future

Now, a potential treatment against stage 1 and stage 2 Human African Trypanosomiasis caused by g-HAT could cure the disease with a single, one-day dose, which will simplify administration and strengthen efforts for sustained elimination of sleeping sickness. It is acoziborole, a cheap, safe and effective drug administered orally. Dr. Wilfried Mutombo Kalonji of the Democratic Republic of the Congo (DRC), Clinical Project Leader and Medical Manager at DNDi, explains that the pivotal Phase II/III clinical trial that evaluated the drugs safety and efficacy in adult and adolescent patients with g-HAT was completed in 2020. It had 208 patients enrolled and was carried out at thirteen sites, twelve in the DRC and one in Guinea. The primary safety and efficacy results are very encouraging. The official publication will be disclosed in the coming months, he adds. Subsequently, two additional clinical studies for g-HAT were launched and are being carried out in DRC and Guinea: seropositive and pediatric patients.

Asked if additional non-clinical studies were carried out to meet the requirements of the European Medicines Agency (EMA) and the Food and Drug Administration (FDA), the researcher answers positively. “The FDA requested an additional 3-month toxicity study in 2 species (mouse and dogs) at doses above the exposure observed in humans. This study is concluded and no new situations that require supervision in humans were observed. Complementary in-silico studies were performed (SymCYP exploration, GastroPlus modeling) for registration purposes. A drug interaction study is planned to start in healthy volunteers in the second quarter of 2022,” he details Regarding the expectation that the drug will receive a regulatory green light, Dr. Kalonji says the dossier will be submitted to the EMA for scientific advice and to the regulatory authority in the DRC to have market authorization and be included in the World Health Organization (WHO) guidelines for g-HAT treatment and sustained elimination of transmission by 2030. “We are committed to the WHO to eliminate HAT by 2030”, he emphasizes.

Regarding the difference between acoziborole and fexinidazole, in terms of formulation, Dr. Kalonji points out that both are oral medications; fexinidazole is given once a day together with food for ten days of treatment, while acoziborole is a single-dose treatment given on fasting conditions. It is slowly eliminated after dosing, which ensures good treatment coverage. For him, the advantage of acoziborole is that it is a single-dose treatment with high safety, which gives it a good profile to accompany the sustainable elimination of THA. “Approval of acoziborole will represent a major step forward for patients. The disease is emerging from the shackles of stigma to become a normal disease. It will also mean a lot of hope for other neglected diseases because their treatments can be reproduced”, he concludes.

Since 2001, the number of cases of human African trypanosomiasis has dropped by 97%, more than 40 million people have been screened and more than 210 thousand patients have been treated. But the disease is still killing people. This single-dose treatment for sleeping sickness could be a real game-changer for people at risk of this deadly disease. Once approved, acoziborole will be distributed free of charge to patients or governments. Currently, there is no effective vaccine against African trypanosomes, and drugs used to treat sleeping sickness are limited in their use and effectiveness due to toxicity, resistance, or administration complexity.

Using cutting-edge genetic technologies, researchers were able to show that acoziborole targets a protein called CPSF3. Structure modeling revealed key differences between human CPSF3 and the parasite, where the drug binds, explaining why the drug is safe and non-toxic to humans. In 2018, the study entitled “Clinical and veterinary trypanocidal benzoxaboroles target CPSF3” was published in the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS).

DRC reports 387 cases of sleeping sickness in Africa in 2021, reported in most provinces

According to a report published in Outbreak News Today, as of February 09, 22 of the 26 provinces that make up the DRC have reported human African trypanosomiasis in 2021. Last year, the country recorded 387 cases. These statistics were released on January 30 2022, on the occasion of the commemoration of the World Day for Neglected Tropical Diseases (NTDs). Given these statistics, the elimination of this disease in the country remains a major challenge. But it is true that in recent years progress has involved therapeutic advances, particularly the administration since January 2020, of fexinidazole, a new effective oral treatment that works in all stages of the disease. The DRC records almost 85% of cases of the disease in Africa. According to the WHO, 5,6 million people are at high risk of infection with this disease.

About the disease

Transmitted by the bite of an infected tsetse fly, after a period of non-specific symptoms, sleeping sickness evolves and causes neuropsychiatric symptoms that include abnormal behavior and a debilitating disturbance in sleep patterns that gives this neglected and threatening disease its name and that threatens million people in 36 sub-Saharan African countries. Many of the affected populations live in remote rural areas with limited access to adequate health services, which makes surveillance and therefore diagnosis and treatment of cases difficult. In addition, population displacement, war and poverty are important factors that facilitate transmission. The incidence of the disease differs from one country to another, as well as in different parts of a single country.

According to the WHO, in the last 5 years, more than 70% of reported cases have occurred in the DRC, with an average of less than 1.000 reported cases annually. Angola, Central African Republic, Chad, Congo, Gabon, Guinea, Malawi and South Sudan reported from 10 to 100 new cases in 2019, while Cameroon, Ivory Coast, Equatorial Guinea, Uganda, United Republic of Tanzania, Zambia and Zimbabwe reported between 1 and 10 new cases. Countries such as Burkina Faso, Ghana, Kenya and Nigeria have reported sporadic cases in the last 10 years. Benin, Botswana, Burundi, Ethiopia, Gambia, Guinea Bissau, Liberia, Mali, Mozambique, Namibia, Niger, Rwanda, Senegal, Sierra Leone, Swaziland and Togo have not reported new cases for more than a decade. Disease transmission appears to have stopped in some of these countries, but there are still some areas where it is difficult to assess the exact situation because unstable social circumstances and/or difficult accessibility muddle surveillance and diagnostic activities.

The control of African trypanosomiasis currently revolves around two main strategies: population screening to ensure early treatment of infected people and helping to reduce the number of people who carry the parasite (fewer people who carry the parasite mean that the tsetse fly is less likely to become infected over time while feeding on blood and less likely to pass the parasite to another individual in their next blood meal). Another strategy is to reduce transmission through the fly using insecticides and installing traps and/or screens in homes to reduce the number of entering insects.

A Doctors Dream: A Sleeping Sickness Pill: From Rediscovery of an Abandoned Molecule to a Revolutionary Medicine: Follow the stories of sleeping sickness patients, doctors and researchers here.