Preclinical development and phase I activities on a selected aminopyrazole compound for visceral leishmaniasis

Introduction and Background of the Project


Drugs for Neglected Diseases initiative (DNDi) in collaboration with Takeda Pharmaceutical Company Limited (Takeda) aims at delivering an anti-parasitic aminopyrazole drug candidate that is orally active, safe, effective, short-course, and field-adapted for the treatment of visceral leishmaniasis (VL).This would have the potential to adress an urgent medical need. Indeed, Leishmaniasis is a complex disease caused by more than 20 different species of the Leishmania parasite, lethal,  if not treated and accounts for 200,000 to 400,000 new cases and 20,000 to 40,000 deaths each year.

This project is the continuation of a lead optimization program started in 2015 and supported by the GHIT Fund. It has been concluded successfully with the selection of a preclinical candidate, DNDI-5561, meeting the target candidate profile (TCP) for further preclinical development. Activities for four advanced back-up compounds continue in parallel to provide, if necessary, differentiated back-ups for this series. DNDi and Takeda will work together to progress DNDI-5561 through regulatory preclinical studies and the single ascending dose stage of first-in-human study.


Project objective

The aim of the project is to progress a selected aminopyrazole compound to Phase I clinical trials and realize some activities including formulation development, drug product manufacture and start single ascending dose study. The objectives for this project are to: (1) process development and manufacture of Active Pharmaceutical Ingredient (API) suitable for preclinical studies, formulation development and Phase I clinical trials (2) create formulations suitable for preclinical safety and toxicology studies and Phase I clinical trials (3) complete preclinical toxicology and safety package to support submission of an Investigational New Drug (IND) (4) manufacture clinical supplies according to Good Manufacturing Practices (GMP) standards for first-in-human studies (5) prepare the Investigational Medicinal Product Dossier (IMPD) and other regulatory documents to obtain regulatory and ethics approval, and (6) start single ascending dose study (SAD).


Project design

DNDi and Takeda will together develop and implement the preclinical study plan for DNDI-5561. Some of the activities will be conducted by Takeda using in-house capabilities and others will be outsourced by the project team to carefully selected world-class contract research organisations (CROs). DNDi and Takeda, both have extensive experience of selecting and contracting CROs to conduct preclinical studies, and DNDi is currently reaching the end of preclinical development of two other preclinical candidates for VL providing a strong current understanding of the CRO landscape. A procurement process will be undertaken to select the most appropriate CROs to conduct the various pharmaceutical development (CMC), genotoxicity, safety pharmacology and toxicology activities based on criteria of quality, cost and speed. The project team will hold monthly meetings to review the progress and results of the preclinical study plan. Once the preclinical development package has been completed a clinical candidate review meeting attended by external experts with various expertise will be held to make a go/no go decision for subsequent Phase I clinical development. An IMPD and regulatory package will be prepared and submitted to the regulatory authorities and ethics committee in the country selected for Phase I SAD study. Once approval has been received the single ascending dose study will commence end of 2019.

How can your partnership (project) address global health challenges?

Visceral leishmaniasis (VL), also known as kala-azar, is caused by the protozoan parasites

Leishmania donovani and Leishmania infantum, and is a potentially fatal disease with a

worldwide distribution. In patients who develop symptoms, presentation is insidious with development of hepatomegaly and splenomegaly, irregular fevers, pancytopenia, weight loss and weakness occurring progressively over a period of weeks or even months. The disease is highly endemic in the Indian subcontinent and in East Africa. In 2015, more than 90% of new cases reported to WHO occurred in 7 countries: Brazil, Ethiopia, India, Kenya, Somalia, South Sudan and Sudan. It is estimated, however, that only 30% of cases are reported.

Pentavalent antimonials remain a component of the primary first-line treatment in East Africa with significant drawbacks in terms of either parenteral route of administration, or length of treatment, toxicity or cost. In addition, there is a dichotomy of efficacy in drug action in visceral leishmaniasis-endemic regions of the world. To date, the medical needs in visceral leishmaniasis are moderately to well-met in South Asia. However, in East Africa and Latin America the efficacy and tolerability of current visceral leishmaniasis therapies remain a challenging area for improvement.  

Few new compounds are in advanced stages of lead optimization or clinical research and there is an urgent need to strengthen the pipeline for this disease. 

What sort of innovation are you bringing in your project?

The proposed approach is clearly differentiated from the existing therapeutics for VL.

DNDi and Takeda are developing a novel class of orally active aminopyrazoles with a presumed novel mechanism of action that demonstrates excellent in vitro and in vivo anti-parasitic activity. DNDi developed this series from a singleton high throughput screening hit which was originally identified in a screen of a library from Pfizer. Thereafter, DNDi and Takeda conducted further research for aminopyrazole series. The aminopyrazoles are a previously unexplored chemical series for treatment of VL and so there is unlikely to be any pre-existing drug resistance or cross-resistance with existing drugs.

It remains essential to add further candidates from different chemical classes to the pipeline to maximise the chance of successfully completing the development of at least one, and preferably two or more drugs to provide a short course, oral treatment. Additionally, combination of new therapeutic agents should be favoured to reduce the risk of developing resistanceto the new drugs.

Role and Responsibility of Each Partner

DNDi will lead and project manage the activities and conduct procurement to select contract research organizations. Takeda will provide CMC consultation regarding API production method, contract manufacturing organization selection and advice on formulation design. Takeda will provide advices for the preclinical studies and conduct some of the studies including the evaluation of the back-up compounds.

DNDi, Takeda, additional academic and CRO laboratories, and expert consultants bring together world-class expertise in neglected diseases R&D and proven capabilities in preclinical studies and clinical development of new drug candidates.  This global team will work closely together to agree on project goals, detailed strategy and plans.