Pharmacokinetic, Efficacy, Safety and Tolerability Study of a Single Dose of Acoziborole in g-HAT Paediatric Patients

Human African trypanosomiasis (HAT), or sleeping sickness, is a life-threatening disease transmitted by tsetse flies and caused by a single-celled extracellular parasite that lives free in the bloodstream and other body fluids, including lymph and cerebrospinal fluid (CSF). There are many species of African trypanosomes; however, only two subspecies of the Trypanosoma brucei (T.b.) species are causative of HAT. T.b. gambiense is endemic in West and Central Africa and causes over 98% of current cases. It progresses at a more indolent pace than that of T.b. rhodesiense.

Approximately 5 million people live in areas, mainly in rural parts of 24 disease endemic countries in West and Central Africa, where HAT due to T.b. gambiense (g-HAT) is still considered a public health problem; whereas, 51 million people are estimated to be at risk of infection on the African continent. With 864 cases of g-HAT reported in 2019, the global goal of sustainable disease elimination by 2030, including the interruption of the transmission of g-HAT, is foreseeable. Consistently falling numbers of cases are thanks to efforts from national control programmes, supported by the World Health Organization (WHO), non-governmental organisations, bilateral cooperation, the private sector (including pharmaceutical companies), and philanthropic organisations.

As the numbers of reported cases diminish, resources for surveillance and specialised screening will also taper. This decrease, coupled with the loss of diagnostic skills and disease management expertise, will lead to a weak and less specialised HAT technical environment. The history of g-HAT has shown that outbreaks or re-emergence of the disease have already happened under different circumstances when surveillance was relaxed, e.g. South Sudan and the Democratic Republic of the Congo (DRC) or simply because the populations at risk live in areas of political instability, limiting access to specialised care. Even with a steady decrease of reported incidence, no model can currently predict that HAT could not re-emerge.

Although g-HAT is predominantly a disease of adults, children are also affected at diverse rates depending on the geographical and behavioural characteristics in the different areas of disease transmission. Globally, the WHO Expert Committee on control and surveillance report states: "rates in children are usually less than half of those in adults, reflecting less exposure to flies during daily activities". In data from the Médecins Sans Frontières Database on HAT control projects, out of 684 second stage HAT patients included, 17.5% were children under the age of 15 hence efforts are needed to develop a paediatric formulation from a new generation of oral HAT treatments. The majority of signs and symptoms associated with HAT occur at similar frequencies in paediatric patients with first and second stage disease compared with adults, including sleep disturbances. The presence of trypanosomes in cervical lymph nodes is less frequent in preschool children than in older children and adults. More infants are seen at the second stage, most likely due to delayed diagnosis and the immaturity of the blood-brain barrier. In some studies, fever, hepatomegaly, splenomegaly and facial oedema were observed more frequently in children aged 2 to 15 years than in adults.

As per the WHO 2019 interim guidelines for the treatment of HAT, the choice treatment is determined by a two-step assessment. The first step is the clinical assessment and the second step is the CSF examination (lumbar puncture), which is required only for patients with clinical symptoms and signs suggestive of the severe meningo-encephalitic stage.

For children \<6 years old and \<20 kg body weight who are second stage g-HAT, a 7-day, twice a day intravenous course of NECT or eflornithine is the sole treatment option. Treatment in first stage g-Hat involves intramuscular injections of pentamidine for 7 days. Both treatments require pre-treatment lumbar puncture and hospitalisation with a specialised health care environment that is not always possible in remote rural African areas where g-HAT is prevalent.

The aim of the current study is to validate the weight-based exposure based on the population pharmacokinetic (pop-PK) modelling, efficacy, and safety of acoziborole in first and second stage g-HAT paediatric patients from 1 to 14 years of age enabling a paradigm shift in the management of paediatric g-HAT patients reducing the subsequent burden on families (i.e. mothers and the entire family will spend less time providing care). Furthermore, if the clinical status permits, administering a single-dose oral drug at the point of diagnosis will avoid the need for costly hospitalisation in specialised health centres, lumbar puncture and parenteral treatments. Compliance and adherence of children to treatment will be more straightforward and will shorten the delay between diagnosis and effective treatment, which will contribute to stopping disease progression and the avoidance of neurological sequelae in this population.

Achieving the challenging objective of g-HAT elimination by 2030 requires a safe, effective, and easy-to-use tool that enables treatment at the point-of-diagnosis for all individuals, including children. As a single administration oral drug, acoziborole would facilitate treatment access for children.