- RFP Year2017
- Awarded Amount$1,498,328
- DiseaseNTD (Chagas disease / Leishmaniasis)
- Development StageLead Identification
- Collaboration PartnersAstellas Pharma Inc., Eisai Co., Ltd., SHIONOGI & CO., LTD., Takeda Pharmaceutical Company Limited, Drugs for Neglected Diseases initiative
- Past Project
Introduction and Background of the Project
The NTD Drug Discovery Booster (“Booster ”) project was launched in 2015 as an experiment aimed at speeding up the process and cutting the cost of finding new treatments for leishmaniasis and Chagas’ disease that put 350 million people at risk in 98 endemic countries affected with the Leishmania parasites, and 70 million people at risk mainly in Latin America affected with the Trypanosoma cruzi parasites as well as patients that are found in Europe, North America, Japan and Australia. The Booster consortium led by DNDi entails exploring high quality libraries simultaneously to rapidly and effectively identify hit series for optimization. The consortium intends to continue the work of the Booster, feeding the mechanism with newly identified hit compounds from various hit finding exercises such as high throughput screening. The consortium currently consists of four Japanese pharmaceutical partners (Eisai Co., Ltd., Shionogi & Co., Ltd., Takeda Pharmaceutical Company Limited and Astellas Pharma Inc.) supported by the GHIT Fund as well as AstraZeneca plc., Celgene Corporation, Merck KGaA and AbbVie Inc. Institut Pasteur Korea is also an important partner in the project by screening the compounds.
The Booster III has the following 3 objectives:
Objective 1: Delivering novel chemical series for leishmaniasis & Chagas disease:
The Booster III project will rapidly expand at least 10 promising hits/hit series against Leishmania donovani and Trypanosoma cruzi, the causative agents of leishmaniasis and Chagas disease, respectively. This will provide series with well-developed structure activity relationships (SAR) ready for immediate in vivo proof of concept studies or, where necessary, focused medicinal chemistry optimization to provide improved tools ready for in vivo studies.
Objective 2: Complete lead evaluation from previous Booster project:
Hit series previously identified by the original Booster project (7-8 series) will complete their investigation towards in vivo proof of concept studies, leading to at least one new series entering into lead optimization (in addition to any booster series which have already entered lead optimization prior to the 2nd quarter of 2018).
Objective 3: Investigate use of Booster mechanism to investigate collaborative target-based in silico screening:
In parallel to the established ligand-based in silico screening approach of the Booster, at least one of the new seeds launched during Booster III will take the form of a target-based query relating to a molecular target of interest to L. donovani and/or T. cruzi. If this method is successful, the resulting chemical matter identified by the Booster consortium will continue into subsequent iterations of screening in the traditional Booster manner.
During the next 2 years, the Booster consortium will run at least 20 iterations of the booster. A single iteration consists of a virtual screen (in silico) at each partner company, followed by experimental testing against parasite(s) of interest. The starting points for these iterations will come from 2 sources:
• At least 10 new seed compounds for L.donovani or T.cruzi (with 1-3 screening iterations each).
• Molecules identified as “improved hits” during previous iterations from the Booster II (e.g. continuation of the Booster process from years 2&3)
The expected output is 1-2 hit series per parasite showing encouraging in vivo activity, (inclusive of any historic hit series progressed into lead optimization from the Booster II). Moreover, the consortium will expand the scope of the Booster project through investigating replacement of the established ligand-based in silico screen with a target-based in silico screening. In this expansion experiment, instead of providing a compound as the first seed, the consortium will instead provide information on a molecular target of interest, with relevance to T.cruzi or L. donovani.
How can your partnership (project) address global health challenges?
The Booster consortium offers a more effective discovery approach to contribute to a potential successful new treatment for leishmaniasis or Chagas disease. For visceral leishmaniasis, existing drugs produce variable efficacy and serious toxicities; only one is administered orally and the rest are given by painful intra-venous/intra-muscular injections. 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. Ideally, what is needed in the treatment of visceral leishmaniasis is a simple oral combination therapy that would prove advantageous/effective in maintaining or improving efficacy, improving tolerability and preventing or delaying the emergence of resistance. Furthermore, a treatment adapted to field conditions, with shorter duration and which could be used pan-geographically, would be optimal.
In the case of Chagas disease there are even fewer treatment options than for visceral leishmaniasis and currently less than 1% of infected people have access to diagnosis and current treatments. Monotherapy with nifurtimox or benznidazole (both from the same nitroheterocycle class) remain the only recognized treatments, but these require long treatment courses, produce variable efficacy, and cause serious side effects resulting in 20-30% of patients discontinuing treatment. It is crucial that new classes of effective, well-tolerated, orally-acting and short-course treatments are progressed into the clinic to provide improved options for patients. New classes of drugs for Chagas disease are also essential to enable development of combination therapies to combat the risk of development of resistance to monotherapies.
What sort of innovation are you bringing in your project?
The Booster process benefits from simultaneously searching a combined compound collection of several million high-quality, drug-like, small molecules and rapidly testing them in the same, standardized in vitro assays to develop a robust SAR for the series. The Booster collection of compounds, which each pharmaceutical company has been collecting and preparing for its own drug discovery research, clearly offers a significant advantage. The combination of different scientific approaches to the in silico screening question results in a broader and more varied screening of compounds with potential parasitic activity compared to what may be synthesized in a traditional hit to lead project.
Over the past two and a half years, the NTD drug discovery booster approach has been successful in demonstating a clear advantage of the use of collaborative in silico screening across pharmaceutical partners. In particular, it has significantly expanded the possibilities within hit-to-lead drug discovery at DNDi, as well as significantly increase the capacity of DNDi’s hit to lead pipeline.The Booster concept enables DNDi to expand hits not only in the immediate chemical space explored in a traditional hit to lead campaign, but also to use the chemical knowledge from these hits to move into new chemical scaffold space (scaffold hop) as well as establish and identify compounds with comparable activity against related parasites (parasite hop).
Role and Responsibility of Each Partner
Takeda, Shionogi, Eisai and Astellas will perform in silico screening of their internal libraries around each seed. They will prepare plates of compounds for shipment to the DNDi screening centre for testing. The companies will also provide intellectual input on the analysis of results coming from the Booster, as well as provide any additional relevant internal information about their compounds chosen for inclusion in a hit series.
DNDi will coordinate the project, conduct the experimental screening of the compounds via one of its dedicated screening centres, and complete the computational and medicinal chemistry analysis of the screening results.