16 October 2009 Management Committee Meeting
Phase 2 Discussions
The Management Committee meeting will aim to complete the following objectives:
To identify the areas of drug discovery research needed to meet the objectives of the Global Malaria Action Plan |
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To identify the current areas of drug discovery research being undertaken globally |
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To review the composition of the Expert Advisory Group (EAG) |
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To agree on the initial Communications Plan for the Project |
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To agree on the next steps and time table for future activities |
Outputs
The team met for a second time in Geneva to review the analysis from the first meeting and to prioritise the workstreams that they would be pursuing in the next stage of the project.
Gap Analysis & Dependencies
The gap analysis conducted at the first meeting in June had been reformatted to capture the levels of activity that the team had identified. The team reviewed this and confirmed that it reflected their thinking. They then identified what needed to be in place in order for work on each topic to proceed more efficiently. These are shown in the column below marked “Dependencies”:-
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Activity Level Identified |
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High |
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Limited |
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None identified |
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Current investment levels |
Control & Elimination |
Elimination alone |
Dependencies |
|---|---|---|---|---|---|---|
| Drug Discovery |
Novel Targets |
P falciparum |
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√ |
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HTS/HCS Gametocyte assay |
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P vivax |
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√ |
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HTS/HCS Gametocyte assay Hypnozoite assay Biology Culture method |
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Other Plasmodium spp |
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√ |
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HTS/HCS Gametocyte assay Hypnozoite assay |
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Current investment levels |
Control & Elimination |
Elimination alone |
Dependencies |
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|
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Mixed infections |
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√ |
Cellular screens Biology Genomics, In vivo models |
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|
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Malaria in pregnancy |
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√ |
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Predictive safety screening DMPK screening |
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Severe malaria |
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√ |
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Predictive screening Underlying pathophysiology |
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Novel drug classes |
P falciparum |
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√ |
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HTS/HCS Gametocyte assay G6PD screening |
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P vivax |
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√ |
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HTS/HCS Gametocyte assay Hypnozoite assay Biology Culture method G6PD screening |
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Other Plasmodium spp |
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√ |
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HTS/HCS Gametocyte assay Hypnozoite assay G6PD screen |
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|
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Mixed infections |
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√ |
Cellular screens Biology Genomics, In vivo models |
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Malaria in pregnancy |
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√ |
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Predictive safety screening DMPK screening |
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Severe malaria |
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√ |
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Predictive screening Underlying pathophysiology |
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IPT (long T½ drugs) |
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√ |
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Primate prophylaxis model |
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Current investment levels |
Control & Elimination |
Elimination alone |
Dependencies |
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Genomics |
Sequencing of Pk, Po, Pm |
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√ |
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In vitro culture systems Target identification & validation Resistance markers |
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Transmission Blocking |
Anti-gametocyte drugs |
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√ |
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Stage specific assays (Pf & Pv) Infectivity assays |
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| Mode of Action |
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Artemisinin resistance |
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√ |
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Artemisinin resistant parasites + phenotype. |
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8-aminoquinolines vs hypnozoites |
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√ |
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Hypnozoite & gametocyte culture methods G6PD predictive model |
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| Underlying Biology |
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Gametocytes |
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√ |
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Hypnozoites |
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√ |
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Hypnozoite model Pv genomics (stage specific expression) |
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Severe malaria pathophysiology |
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√ |
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Disease model |
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| Platform Technologies |
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Culture media for Pk, Po, Pm |
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√ |
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Preclinical |
DMPK |
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√ |
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Capacity Standard infection models to use |
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Toxicology |
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√ |
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Capacity |
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Medicinal chemistry |
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√ |
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Capacity |
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√ |
|
Capacity |
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Current investment levels |
Control & Elimination |
Elimination alone |
Dependencies |
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Biology |
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√ |
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Capacity Surrogate animal models |
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| Platform Technologies |
Target identification |
Crystallography |
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√ |
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Capacity |
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Bioinformatics |
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√ |
|
Capacity |
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Genomics |
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√ |
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Capacity |
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Target evaluation |
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√ |
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Capacity |
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Drug screening |
Blood stage |
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√ |
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Liver stage |
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√ |
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Pregnancy |
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√ |
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G6PD activity |
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√ |
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| Drug usage in Elimination |
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Risk / benefit profile for MDA drugs |
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√ |
Updated TPPs for all types of drugs |
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The models that were identified in the analysis above should be predictive, robust, and reproducible - allowing them to be widely used within the malaria R&D community.
Based on the discussion at the first meeting, it was agreed that all research needs for the Control phase of the GMAP could be considered as also being required for the Elimination phase. Only those that would be exclusively required for the Elimination phase have been separately identified.
Workstream Prioritisation
The team then moved on to prioritise workstreams that emerged from the gap & dependency analysis. The criteria for prioritisation were:-
Ease to get results |
Cost of achieving results |
Time to get results |
Unmet need |
Impact |
Widespread application & dissemination |
Current level of activity |
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The team looked again at the gap analysis and the dependencies and grouped the topics into potential workstreams for further in-depth analysis. A new potential workstream was added – a robust and open process to bring together all the information currently available on potential new hits from the various HTS campaigns around the world. This process would then ensure that there was a process for using this information to select the right hits and progress them through to candidate drugs.
The team then prioritised the workstreams, selected the top 5, and agreed on leaders for each:-
Workstream |
Leaders |
Pf novel targets & classes |
Christian Doerig Kelly Chibale |
Pv novel targets & classes |
Christian Doerig Kelly Chibale |
New hit-to-candidate process |
Steve Ward Ian Bathurst |
Artemisinin resistance |
Steve Ward Michael Lanzer |
Stage specific screening models |
Donatella Taramelli Henri Vial |
Each workstream’s leaders were tasked to put together early in 2010 one-or-more workshops, involving relevant experts in the field, to produce an in-depth workplan for the particular workstream. The meetings should not be more than 20 persons to promote discussion and would run for 1 or 2 days. Attendees might extend beyond malaria (e.g. experts in liver immunology and working on liver cancer might have expertise to bring on the study of hypnozoites).
The expected outputs of these meetings would be:-
Identify in detail the priorities for research in the relevant area
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Identify the current work being undertaken in the field and who is funding it
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Identify areas for new research and which lack funding but need to be prioritised
The reports from each of these workshops would then be consolidated into an overall project report that might form the subject of a symposium at 2010 ASTMH. It would also be published in a major journal and could be presented (in whole or in part) at earlier meetings if the findings merited it.
It was also agreed that a list of funders (actual and potential) for the work that will be identified in the various workstreams would be drawn up by the Liverpool team. It will then be circulated to other members of the Consortium to add to the list to give a comprehensive picture of the malaria drug discovery funding landscape. This will then be used as a resource to set up meetings with the funders to discuss the results of the project.
The gametocyte assay should also include the measurement of parasite viability.
It was agreed that medium content screens would also be a value in many cases where HCS have been identified as a dependency.