- RFP Year2017
- Awarded Amount$6,047,757
- DiseaseNTD (Leishmaniasis)
- Development StagePreclinical development
- Collaboration PartnersTakeda Pharmaceutical Company Limited, Drugs for Neglected Diseases initiative
- Past Project
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.
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).
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.
1. Project objective
The aim of the project was to progress an aminopyrazole compound (DNDI-5561) to Phase I clinical trials following its nomination as a preclinical candidate for visceral leishmaniasis.
Main objectives for reaching this goal were: process development and manufacture of Active Pharmaceutical Ingredient (API) suitable for preclinical studies, formulation development for preclinical studies and Phase I clinical trials, preclinical toxicology and safety package to support submission of an Investigational Medicinal Product Dossier (IMPD), manufacture GMP quality (Good Manufacturing Practices) clinical supplies for first-in-human studies, prepare all regulatory documents to obtain regulatory and ethics approval, and finally start a single ascending dose study (SAD).
2. Project design
DNDi in partnership with Takeda implemented together the preclinical study plan for DNDI-5561. Following procurement processes, the project team selected world-class contract research organisations (CROs) for the various pharmaceutical development activities and the preclinical studies (ADME, genotoxicity, safety pharmacology and toxicology). Review of progress and results during regular meetings bringing together the project core team, drug development experts from Takeda and consultants from DNDi’s network were held to ensure prompt and thoughtful decisions.
3. Results, lessons learned
Following a successful process development, three batches of API were manufactured: a development batch (100 g), a 4 kg demo batch to support nonclinical studies and finally a 4 kg GMP batch whose release occurred in early 2020 with validated analytical methods. Three potential genotoxic impurities (PGI) were identified. Consequently, an appropriate control strategy was established and the PGIs synthesized to be specifically tested. The risk identified was eliminated when these impurities were shown to be negative in a GLP Ames test.
A nonclinical formulation was developed, and exposure validated in a rat pharmacokinetic study.
For validating our choice to work with the R-enantiomer (DNDI-5561), the S-enantiomer form was synthetized and evaluated in in vitro parasitology assays, physicochemical profiling tests and a safety pharmacology panel. The absence of in vivo interconversion of DNDI-5561 to the S-form was finally demonstrated in the rat.
In vitro studies showed the potential for DNDI-5561 to be a CYP3A4 inducer, however only at concentrations which are likely not relevant in a clinical setting. Reaction phenotyping with recombinant CYP450 isoforms confirmed the slow metabolism found in human liver microsomes.
Bacterial reverse mutation test (Ames Test) did not bring any findings whilst the Micronucleus Assay in Human Lymphocytes judged DNDI-5561 as potentially clastogenic.
DNDI-5561 was determined to be probably phototoxic according to the 3T3 NRU test, however of questionable toxicological relevance for a systemic drug.
Due to the observation of acute, severe, and irreversible retinal toxicity in the dog from a single administration of 50 mg/kg and the inability to understand the mechanistic cause, the team decided to discontinue the development of DNDI-5561, as well as that of any analogous molecules due to the lack of an adequate discriminating assay.
The main lessons learnt during this project was: (1) to avoid the discovery of acute toxicity at this stage, a Dose-Range Finding (DRF) study in non-rodent species could be done before preclinical nomination with the caveats that such studies requiring substantial investment and material which are usually unavailable at Lead Optimisation stage, (2) collaborative work done with diversity and a reasonable number of team members ensures good and rapid decisions.