Awarded Amount$1,761,309DiseaseMalariaInterventionDrugDevelopment StageLead OptimizationCollaboration PartnersDaiichi Sankyo, Inc. , Medicines for Malaria Venture (MMV)Past Project
Introduction and Background of the Project
Since 2000, malaria-associated mortality has been reduced by more than 50%. However, approximately 214 million malaria cases were estimated to occur in 2015, leading to 438,000 deaths, the majority of whom were children (> 80% of all cases).1 In March 2015, Daiichi Sankyo and MMV initiated a GHIT funded Hit-to-Lead platform (HTLP) project investigating three series of compounds with antimalarial activity. Following a focused, multi-disciplinary effort involving researchers from Daiichi-Sankyo India (New Delhi, India), the Centre for Drug Candidate Optimization (Melbourne, Australia) and the Eskitis Institute (Brisbane, Australia) two novel series were identified meeting GHIT and MMV early lead criteria for antimalarial drugs.2 In October 2016 both compound series were progressed to the GHIT Product Development Platform (PDP).
The project objective is to deliver, within 24 months following the start of the phase, a pre-clinical candidate molecule with attributes meeting the Target Candidate Profile (TCP) for new antimalarial drugs.3
In order to mitigate the risk of series attrition resulting from to sub-optimal physicochemical / biochemical properties, pharmacokinetics or toxicity two early lead series are being investigated in parallel during the PDP phase of the project. The series are being optimized by an iterative cycle of compound design and testing, involving medicinal chemistry, in vitro / in vivo parasitology and DMPK. Strategic and scientific oversight is provided by the MMV Expert Scientific Advisory Committee (ESAC) to help ensure that the compound series are aligned with the global portfolio of antimalarial drugs in clinical and pre-clinical development.
How can your partnership (project) address global health challenges?
Despite significant scientific progress, new, affordable and safe malaria medicines are urgently required to overcome increasing resistance against artemisinin based combination treatments, treat vulnerable populations, interrupt the parasite life cycle by blocking transmission to the vectors, prevent infection and target malaria species that transiently remain dormant in the liver. For these reasons the project is focused on series that have potential to address gaps in the global malaria portfolio. The first series rapidly clears blood stage parasites, operates by a novel mechanism of action (MoA) and is efficacious against drug resistant strains of malaria. The second series clears blood stage parasites at slower rate but has opportunity for development as a partner drug with long duration to deliver total cure, block transmission and provide post-treatment prophylaxis. The quality of the chemical starting points for antimalarial drug discovery projects is a key factor in improving the likelihood of clinical success. Both compound series were selected using the stringent GHIT and MMV early lead criteria for antimalarial drugs.2
What sort of innovation are you bringing in your project?
Each and every partner brings their particular expertise to the project team. Working together in a peer reviewed environment, the multi-disciplinary, multi-national group of experienced and motivated researchers have extensive and complimentary approaches to neglected disease research. This innovative approach escapes from the traditional drug discovery paradigm of “introvert innovation” and can shorten the drug discovery timeline as well as increasing the probability of success.
MMV is recognized as a leading Product Develop Partnership in the field of antimalarial drug research and development, focused on the development of the next generation of medicines to support eradication and eventual elimination of the disease. In line with the World Health Organization (WHO)’s Global Technical strategy for Malaria4 MMV has helped define Target Product Profiles for new antimalarial medicines and has built up an extensive network of partners.
Daiichi Sankyo is a global pharmaceutical company with corporate origins in Japan, a full partner of GHIT and committed to contribute to the research of neglected diseases.
The Centre for Drug Candidate Optimization has translational expertise in the measurement and interpretation of ADME/PK properties and the group has provided DMPK support on antimalarial and neglected disease projects for over 10 years resulting in the identification of multiple antimalarial drug candidates in clinical development (e.g. OZ439, DSM265 and MMV048).
The Avery group at the Eskitis Institute has a proven track record for in vitro parasitology and has been a key member of project teams responsible for the discovery of novel antimalarial drug candidates currently in clinical development (e.g. MMV048). The group has established a number of field-leading, high content, image based assays for both asexual blood5 and sexual blood6 stages of the malaria parasite life-cycle and were responsible for running the original high throughput screen (HTS) from which the hit series were identified.
Role and Responsibility of Each Partner
The project is a close collaboration between Daiichi-Sankyo, MMV and the partner test centers with overall project management the responsibility of Daiichi-Sankyo and MMV. Daiichi-Sankyo is the Designated Development Partner, which is responsible for the performance of the Project and for each collaboration partners’ compliance. In addition to project management, MMV provide strategic input and connect the team with malaria researchers in the MMV network giving access to expert advice and state of the art assays. Compound design and synthesis is led by a team from Daiichi-Sankyo India. The primary parasitology (asexual and sexual blood stage assays) is carried out by the group directed by Professor Vicky Avery at the Eskitis Institute for Drug Discovery. All other in vitro and in vivo parasitology and transmission blocking assay data is generated by MMV partners. The physical properties and DMPK profiling is performed at the Centre for Drug Candidate Optimization under the direction of Professor Susan Charman.
Others (including references if necessary)
1. WHO. World Malaria Report 2015. WHO (2015).
2. Katsuno, K. et al. Hit and lead criteria in drug discovery for infectious diseases of the developing world. Nat. Rev. Drug Discov. 1–8 (2015).
3. Burrows, J. N., van Huijsduijnen, R. H., Möhrle, J. J., Oeuvray, C. & Wells, T. N. C. Designing the next generation of medicines for malaria control and eradication. Malar. J. 12, 187 (2013).
4. WHO. Global technical strategy for malaria 2016-2030. WHO Geneva 1–35 (2015).
5. Guiguemde, W. A. et al. Chemical genetics of Plasmodium falciparum. Nature 465, 311–5 (2010).
6. Duffy, S. & Avery, V. M. Identification of inhibitors of Plasmodium falciparum gametocyte development. Malar J 12, 408 (2013).
1. Project objective
The project objective was to deliver, within 24 months following the start of the phase, a pre-clinical candidate molecule with attributes meeting the Target Candidate Profile (TCP) for new anti-malarial drugs.
2. Project design
In order to mitigate the risk of series attrition resulting from to sub-optimal physicochemical / biochemical properties, pharmacokinetics or toxicity, two early lead series were being investigated in parallel. The series were being optimized by an iterative cycle of compound design and testing, involving medicinal chemistry (DS), in vitro / in vivo parasitology (Eskitis / MMV) and DMPK (Monash). Strategic and scientific oversight were provided by the MMV Expert Scientific Advisory Committee (ESAC) to help ensure the alignment of the compound series with the global portfolio of antimalarial drugs in clinical and pre-clinical development.
3. Results, lessons learned
Two compound series that showed in vivo efficacy in SCID mouse model during the lead identification stage were investigated. Target candidate profiling and mode of action (MOA) analyses revealed that TCPs and MOA of these series could be different from one another. Toxicological profiling made the team terminate further investigation of Series 2 due to the concerns from the early in vitro toxicity studies. The team focused on the lead optimization of Series 1 with careful analysis of SAR and physicochemical properties. From this effort, one compound showed better in vivo efficacy than our frontrunner compound in SCID mouse model, however it was very difficult to obtain the compounds which met the Late Lead Criteria. The team decided to terminate this collaborative project based on the difficulty of obtaining compounds that would meet the Late Lead Criteria. As for the lessons learned, it could be important to screen much larger set of compounds to obtain multiple hit compounds and scaffolds in order to mitigate the risk of series attrition. Enthusiastic scaffold hopping exploration from the late stage of lead identification through early lead optimization could be necessary as well if physicochemical properties and PK profile of the hit compounds were poor.
Identification of pre-clinical candidate as an anti-malarial agent