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Exploiting the Pathogen box
Dr Richard Gordon
Director
Strategic Health Innovation Partnerships
9 May 2014
www.ship.mrc.ac.za
http://www.ship.mrc.ac.za/http://www.ship.mrc.ac.za/
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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?
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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
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Hit-to-Lead
Lead Generation Lead Optimization
Preclinical Candidate Profiling
Lead Optimization Screening
Clinical trials
PI PII PIII PIV Formulation Toxicology API synthesis
1 year 2-3 years 1.5 years 7-9 years
Target Identification Chemistry
Pre Clinical
Drug Discovery Value Chain Neglected diseases gaps
Academia Industry
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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
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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
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Hit-to-Lead
Lead Generation Lead Optimization
Preclinical Candidate Profiling
Lead Optimization Screening
Clinical trials
PI PII PIII PIV Formulation Toxicology API synthesis
1 year 2-3 years 1.5 years 7-9 years
Pre Clinical
Leveraging Resources Case Study 1: Tuberculosis
2012
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Microsomal stability Cytotoxicity
Screen/Synthesis
Kinetic solubility
po DMPK
Efficacy in vivo model
• MIC (replicating) ≤ 10µM, and
• Sol ≥ 5 µM; or
• Mic. Stab. >75% rem after 40min; or
• Cytotox MIC > 20x [Mtb MIC]
• MIC ≤ 2.5 µM
• Sol ≥ 10 µM
• Mic. Stab. ≥ 75% rem after 40min
• Cytotox MIC ≥ 20x [Mtb MIC]
Target ID
Susceptibility to
mycobacterial efflux
MIC99 M. tuberculosis H37Rv
7H9 (BSA) media
MIC99 M. tuberculosis H37Rv
GAST-Fe (non-BSA)
media
MIC against clinical and drug-resistant strains
Intracellular Screen Test (3 Drugs) in Macrophages
M. Tuberculosis H37Rv/MDR Clinical strain
Intracellular MIC90 (1 Drug, 0.5, 1, 2, 4 µM) in Macrophages
M. Tuberculosis H37Rv/MDR Clinical strain
Structure
elucidation and
FBDD
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Hit-to-Lead
Lead Generation Lead Optimization
Preclinical Candidate Profiling
Lead Optimization Screening
Clinical trials
PI PII PIII PIV Formulation Toxicology API synthesis
1 year 2-3 years 1.5 years 7-9 years
Pre Clinical
Leveraging Resources: Case Study 2: Malaria
2008
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Hit-to-Lead
Lead Generation Lead Optimization
Preclinical Candidate Profiling
Lead Optimization Screening
Clinical trials
PI PII PIII PIV Formulation Toxicology API synthesis
1 year 2-3 years 1.5 years 7-9 years
Pre Clinical
Leveraging Resources: Case Study 2: Malaria
2014
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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
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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
