Introduction and Background of the Project

Introduction

Drugs for Neglected Diseases initiative (DNDi) in collaboration with Eisai Co., Ltd. aim to develop a drug candidate that is orally active, safe, effective, short-course, and field-adapted for the treatment of visceral leishmaniasis (VL). Leishmaniasis is a complex neglected tropical disease caused by more than 20 different species of the Leishmania parasite, deadly if not treated and accounts for 50,000 to 90,000 new cases and 10,000 deaths annually. The long term goal of DNDi’s leishmaniasis program is to contribute to the World Health Organisation NTD roadmap of eliminating VL as a public health problem and targeting zero deaths globally due to primary VL by 2030.

Eisai is a leading global pharmaceutical company with a dedicated Global Health unit and state of the art capabilities for process chemistry, manufacturing and formulation development. DNDi is a Product Development Partnership with a mission to serve the needs of neglected patients has over 15 years of experience of delivering new treatments to leishmaniasis patients.

DNDI-6174 is an exciting candidate which presents a novel mechanism of action and an important opportunity to develop a new, orally acting treatment for leishmaniasis. In this proposal the project partners, DNDi and Eisai, aim to complete the preclinical development of DNDI-6174 within the time span of two years to enable its nomination as a Clinical Candidate ready for Phase I studies in healthy human volunteers.

Project objective

The objectives for this project are to:

Objective 1 :  develop a suitable synthetic route and manufacture Active Pharmaceutical Ingredient (API) appropriate for preclinical studies, formulation development and Phase I clinical trials

Objective 2: develop suitable formulations for preclinical safety and toxicology studies and for Phase I clinical trials

Objective 3: complete the preclinical toxicology and safety package

Objective 4: manufacture clinical supplies for first-in-human studies with the initiation of API and Drug Product stability studies

Objective 5: review the results of the preclinical development programme including the preparation of regulatory documents (Investigator Brochure and Investigational Medicinal Product Dossier) and nominate DNDI-6174 as a Clinical Candidate ready for Phase I trials in healthy human volunteers.

Project design

The first CMC step is to optimize the current synthetic route for yield improvement and elimination of some chromatographic steps. This optimized route is scaled-up and used to synthesize material for GLP studies and clinical formulation development (2.5 kg) and GMP manufacturing (4 kg).  An approach to scout new efficient route with the long-term goal of further reducing COGs is also considered, while analytical activities such as method development, reference standard qualification and impurity understanding are conducted to support preclinical drug substance supply.

In parallel, salt selection and polymorph screening are conducted to provide a suitable salt with known polymorph information to be implemented in manufacture of drug substance. 

With the goal to be ready for a first-in-man study at the end of the project, a GMP drug substance batch is manufactured, and an appropriate formulation for an immediate release dosage form developed.

Analytical development and validation activities (API + DP) and initiation of stability studies (GMP API and Ph-I non-GMP formulation informal stability to set provisional shelf-life of GMP drug product) are included to support regulatory filing, clinical batch manufacture, packaging, and release.

Before launching the IND/CTA-enabling studies, the exposure level with the new API and oral formulation is verified in pharmacokinetic studies.

The GLP preclinical package includes analytical methods development and validation, safety pharmacology and genotoxicity batteries, dose-range finding study in the dog, and 28-day pivotal toxicity studies in the rat and dog with a recovery period to assess reversibility of possible findings.

For reducing the overall animals' number and cost, and since no risk was suspected, the in vivo genotoxicity endpoint and the CNS assessment are included in the rat pivotal toxicity study.

The 28-day duration will allow an administration of DNDI-6174 up to 14 consecutive days in human, meeting the maximum acceptable duration of the TPP.

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, 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. DNDI-6174 would directly contribute to the advancement of new compounds addressing the urgent need to strengthen the pipeline for this disease. DNDi in collaboration with its partners, has produced eight new treatments for NTDs which are now available to patients, with its leishmaniasis program addressing the control and elimination of this disease as well as bringing the death rates down to zero by 2030.

What sort of innovation are you bringing in your project?

DNDi through its Drug Combination Development Platform (DCDP) with its partners is aiming to develop a combination therapy based on newly developed New Chemical Entities (NCEs) to achieve short course therapy with satisfactory efficacy having utility for all regions with disease and avoid emergence of drug resistance. This will improve and simplify current case management and support elimination efforts. The current pipeline of oral NCEs for VL at the translational stage is unprecedented but the risk of attrition remains. Hence, anticipation of a high rate of attrition in NCE development is a compelling argument to continue efforts to add to the pipeline.  DNDI-6174 is an ideal candidate for development as it belongs to a novel chemical class (pyrrolopyrimidine) and acts through a new mechanism of action (cytochrome bc1 complex inhibitor) and offers the possibility to avoid negative toxicological findings that may stop other candidates.

Role and Responsibility of Each Partner

Eisai is responsible for process chemistry, API manufacture and formulation development, including its coordination and procurement. Whilst DNDi is responsible for preclinical studies (ADME, modelling, parasitology, safety pharmacology and toxicology studies), as well as the overall project management.