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.

Final Report

1. Project objective:

Visceral leishmaniasis (VL) remains one of the top parasitic diseases with outbreak and mortality potential. Safe, effective, short-course oral treatments adapted to different patient populations and regions are still missing. DNDI-6174 is a drug candidate that brings a new mechanism of action (cytochrome bc1 complex inhibitor) and represents an important opportunity in the development of new treatments for leishmaniasis. The objective of the project was to develop DNDI-6174 through the preclinical stage and to prepare for future Phase I clinical development.

2. Project design:

Through a strong partnership, DNDi led project management and non-clinical development of DNDI-6174, and Eisai Co., Ltd. (Eisai) led pharmaceutical development of the compound. Under DNDi responsibility, IND-enabling safety testing was conducted by CROs, and complementary pharmacodynamic studies were performed by academic partners. Eisai involved several of its facilities dedicated to drug substance, drug product, analytical development, and project management to facilitate pharmaceutical development activities for DNDI-6174. 

3. Results, lessons learned:

A suitable salt form of DNDI-6174 was selected and developed. The synthetic route was optimized to establish a reproducible process that enhances throughput and reduces the cost of goods. Successful manufacturing of several lots was completed for use in GLP studies and drug product development. A GMP batch was manufactured for use in future clinical trials. Acceptable stability of the GMP material of up to 18 months was demonstrated. Tablets formulated at an appropriate dose were developed with optimization of the manufacturing process at a 14,000 tablets scale. This Phase I candidate formulation was shown to be stable under long-term conditions for at least 12 months and accelerated conditions for 6 months.

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

A comprehensive programme encompassing safety pharmacology, drug metabolism, pharmacokinetic, and toxicology studies was conducted to support the clinical development of DNDI-6174. The pivotal 28-day duration toxicity studies support the administration of DNDI-6174 up to 14 consecutive days in humans (the maximum acceptable duration in the TPP). 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, progressing DNDI-6174 as a clinical candidate.

The close partnership between Eisai and DNDi proved to be extremely beneficial in sharing complementary skills and expertise. This pairing was an asset for rapidly solving issues inherent to drug development and ensuring an excellent collaboration with GHIT.