DNDI-6174

The pre-clinical programme was successfully completed and DNDI-6174 was nominated as a clinical candidate. The pivotal 28-day toxicity studies support the administration of DNDI-6174 up to 14 consecutive days in humans – the maximum acceptable duration in the target product profile. Target organs and potential risks to humans, non-observed adverse effect level (NOAEL), safety margin, first-in-human starting dose, and stopping criteria were defined.

Acceptable stability of the GMP material up to 18 months was demonstrated, and the tablet Phase I candidate formulation was shown to be stable under long-term conditions for at least 12 months and under accelerated conditions for 6 months.

The excellent pharmacological profile of DNDI-6174 was reinforced by showing its potential to approach sterile cure for visceral leishmaniasis, and for the additional indication of cutaneous leishmaniasis.

Our teams and partners focused on extending our knowledge of DNDI-6174’s nonclinical profile and progressing on the path to a first-in-human clinical trial. From a pharmaceutical development perspective, all ongoing stability studies were successful. This includes confirmation of the six-month stability of the GMP material and studies of the 5 and 50 mg tablets to establish storage and packaging conditions. The outcomes of our work with GSK and Dundee University on the discovery and preclinical development of DNDI-6174 that lead to its nomination as a drug candidate for visceral leishmaniasis were published in Science Translational Medicine.

In 2022, Eisai Co., Ltd manufactured three batches DNDI-6174, with 2.9 kg allocated for regulatory pre-clinical studies, 3 kg for drug product development, and 5.7 kg for future clinical trials. After developing and evaluating different formulations, prototypes of 5 and 50 mg tablets were created for stability testing. In parallel, all necessary pre-clinical studies to support a Phase I clinical trial application were completed and their results will be used to determine whether Phase I clinical trials should proceed. Additionally, an in vivo study completed in 2022 confirmed DNDI-6174’s potential in treating cutaneous leishmaniasis.

2021 saw progress made on the drug substance with the selection of an HBr salt that showed very good solubility, scalability, and manufacturability properties. Moreover, the former synthetic route has been optimized and a reproducible process has been established, increasing throughput and reducing cost of goods. Pre-clinical activities have started with the selection of CRO partner Aptuit, an Evotec Company, and the development of the non-clinical formulation. 

Further characterization of DNDI-6174 and preparations to initiate pre-clinical activities continued in 2020. With support from Japan’s Global Health Innovative Technology Fund (GHIT Fund), DNDi and Eisai will start collaborating in Q2 2021 to conduct pre-clinical development activities and prepare the way for future Phase I clinical studies in healthy human volunteers. 

Planning is underway to start pre-clinical activities in 2020.