Exploiting the Pathogen box

Transcription

1 Exploiting the Pathogen box Dr Richard Gordon Director Strategic Health Innovation Partnerships 9 May

2 Background Worked with MMV in many areas Servicing Partner Consultant Collaborator Now a Co-funder in product development Strong understanding of MMV: philosophy of leveraging & pooled funding good governance and reporting the specific resource needs for managing project Also bring a member state view from Africa Where are key gaps in the drug discovery?

3 A project with great potential. Pathogen research is plagued by 3 key limitations Lack of pharmaceutical commercial interest and investment Generally academic led with little experience in drug development Only interested in late state projects Limited knowledge of new molecular drug targets Vital to overcome drug resistance Vital to discover drugs with new mechanism of action Limited availability of chemical starting matter Impure or toxic Chemistry driven with little supporting data

4 Drug Discovery Value Chain Neglected diseases gaps Lead Generation Lead Optimization Pre Clinical Clinical trials Screening Hit-to-Lead Lead Optimization Candidate Profiling Formulation API synthesis Toxicology PI PII Preclinical PIII PIV 1 year 2-3 years 1.5 years 7-9 years Target Identification Chemistry Academia Industry

5 Resource mobilisation Proposal objectives focus on prosecuting: 10 Active-to-Hit projects each year: delivering 5 robust projects per year, for 5 years 8 Target deconvolution projects each year: delivering 5 new biological targets a year, for 5 years Sustainable level of assets to support work plans 50 compound series investigated (12.5% of the Box) 40 target deconvolution studies (10% of the Box) The quality of the Box will enable these objectives to be met and provide opportunities beyond this proposal

6 Resource mobilisation - opportunities Delivery of the MMV Pathogen Box and accompanying profiling data: USD 4,616,720 direct funding from BMGF Delivery of the 400 compounds in the MMV Pathogen Box to testers: free to all Pathogen screening to be performed by partner: in-kind contribution Target exploitation with SGC or IMI (structural work or further screening): in-kind contribution Open innovation software through partnering with experts including ChEMBL, RSC, OSDD: in-kind contribution Delivery of new projects to partners for follow-up: co-ordination with PDPs and support for grant applications where necessary Many opportunities to leverage resources: Case studies in Matched funding through local agencies Skills generation

7 Leveraging Resources Case Study 1: Tuberculosis Lead Generation Lead Optimization Pre Clinical Clinical trials Screening Hit-to-Lead Lead Optimization Candidate Profiling Formulation API synthesis Toxicology PI PII Preclinical PIII PIV 1 year 2-3 years 1.5 years 7-9 years 2012

8 Screen/Synthesis MIC 99 M. tuberculosis H37Rv 7H9 (BSA) media Microsomal stability Kinetic solubility MIC 99 M. tuberculosis H37Rv GAST-Fe (non-bsa) media Cytotoxicity MIC (replicating) 10µM, and Sol 5 µm; or Mic. Stab. >75% rem after 40min; or Cytotox MIC > 20x [Mtb MIC] MIC against clinical and drug-resistant strains MIC 2.5 µm Sol 10 µm Mic. Stab. 75% rem after 40min Cytotox MIC 20x [Mtb MIC] po DMPK Target ID Susceptibility to mycobacterial efflux Structure elucidation and FBDD Intracellular Screen Test (3 Drugs) in Macrophages M. Tuberculosis H37Rv/MDR Clinical strain Intracellular MIC 90 (1 Drug, 0.5, 1, 2, 4 µm) in Macrophages M. Tuberculosis H37Rv/MDR Clinical strain Efficacy in vivo model

9 Leveraging Resources: Case Study 2: Malaria Lead Generation Lead Optimization Pre Clinical Clinical trials Screening Hit-to-Lead Lead Optimization Candidate Profiling Formulation API synthesis Toxicology PI PII Preclinical PIII PIV 1 year 2-3 years 1.5 years 7-9 years 2008

10 Leveraging Resources: Case Study 2: Malaria Lead Generation Lead Optimization Pre Clinical Clinical trials Screening Hit-to-Lead Lead Optimization Candidate Profiling Formulation API synthesis Toxicology PI PII Preclinical PIII PIV 1 year 2-3 years 1.5 years 7-9 years 2014

11 How will the money be used? Target deconvolution studies USD 400,000 8 compounds each year global key disease experts Compound acquisition USD 100,000 Support of 10 Hit expansion projects Synthetic chemistry USD 390,000 Hand-crafted chemistry on 10 Hit expansion projects In vitro ADMET studies USD 100,000 Profiling on frontrunners from 10 projects Project leader, medicinal and computational USD 200,000 Travel and indirect costs: USD 170,000 Total / year for 5 years USD 1,360,000

12 Conclusion A project with great potential Will provide: A list of new molecular targets for a number of pathogens High quality drug-like leads for further optimisation A galvanizing catalyst in many countries to initiate new life saving programs

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