Title: Drug Discovery Strategies
1- Drug Discovery Strategies
- for Tropical Diseases
- Solomon Nwaka
ASTMH Meeting Nov. 2006
2Outline of Presentation
- High burden of tropical diseases and why?
- Gaps in RD
- Changing landscape for tropical diseases RD
- TDR 10 year strategy
- Drug discovery strategies models
- Industry/Academia/PPP models
- Integrated networks/partnerships/north-south
- Conclusions
3Burden of Diseases in Developing World
4Why High Disease Burden?
- Control measures are not accessible or lacking
- No vaccines for most
- Robust diagnostics tools are lacking
- Available drugs often fail due to
- Resistance
- Compliance issues
- Safety concerns
- Formulation
- Poor health services infrastructure
5Vicious Cycle of Disease Poverty
Poverty
Infectious Diseases
6Impediments to New Product RD and Delivery
Health
Registration Production regulation
Wide appropriate use
Product introduction strategies
Product Leads development
Research
system
Unattractive return on investment for
commercial RD
Lack of planning for use in low income countries
Weak health services infrastructures
7Consequent Gaps in Drug RD for Tropical Diseases
GAP I GAP II GAP III GAP IV
Capacity for uptake of new medicines Capacity
for post-approval processes
Good animal models to assess safety and
efficacy Good evaluation tools
Screening tools Valid. drug targets New
compounds
Clinical trials capacity in developing
countries
Research and discovery
Preclinical development
Registration, launch, utilisation
Phase II
Phase I
Phase III
IFPMA Publication
8Changing RD Landscape
- Enhanced global RD activities
- New funding from Foundations Governments
- Genome sequences of several parasites
- PPPs
- Increasing industry engagement
- New mechanism being discussed
- Advance purchase commitments
- A Global Fund for product RD
- Technology transfer to stimulate RD innovation
and sustainability in developing countries
9New Vision for TDR
An effective global research effort on infectious
diseases of poverty in which disease endemic
countries play a pivotal role
10Modelling Needs, Gaps and TDR's Role
New and improved tools
New and improved interventions
New and improved strategies
New knowledge /discoveries
11Many New Players, But Significant Needs / Gaps
Grand Challenges
New and improved tools
New and improved tools
New and improved tools
New and improved interventions
New and improved strategies
DNDi
New knowledge / discoveries
NIH, Trust, Research councils, etc
12Strategic Functions Identified
Foster Empowerment through leadership
development at individual, institutional and
national levels
Foster innovation for products, emphasizing DEC
engagement
Foster research to develop and evaluate
interventions in real-life settings
Foster research for access to interventions
Stewardship through an analytical information
service and platform for discussion on global
research needs, priorities and activities
13Innovation for Products
- Goals
- Leads discovered transferred to development
- North-south innovation networks/partnerships
- DEC led product RD projects
- Use of indigenous knowledge
14Tripartite Strategy for Drug Discovery
- Extending the indications of existing drugs to
tropical diseases, example ivermectin - "Piggy backing" on programs in clinical
development for other indications, e.g. HDAC,
Falcpain inhibitors - de novo discovery of new chemical entities
15Drug Discovery Models
- Industry model
- Dedicated in house facility
- Specific project or mini-portfolio partnership
- Broad neglected diseases discovery partnerships
- Academic model
- Compound screening
- Dedicated units for Genomics, HTS, Chemistry
- Specific PPP projects, and networks activities
- PPP/other model involving portfolio management
- One or few diseases
- Multiple diseases with coordinated network of
academia, industry in the north and south.
16Integrated Network/Partnership Model
PK/ Metabolism Network
Compounds (Known rationale,diverse,
naturalproducts)
In Vitro/Vivo Screening Network
Capacity Buiding/ Fellowships
HITS
HITS
Quality Leads
LEADS
Drug Candidates
Optimization
HTS
Validated Drug Targets
Interface with other players
Target Portfolio Network
Medicinal Chemistry Network
Nwaka and Hudson 2006
17TDR Funded Network for Compound Evaluation
Primary in vitro assays Hit ident.
STI- Malaria, Afr tryps., Chagas, Leish.
LSHTM/TBRI - Schisto.
LMPH - Malaria, Afr tryps., Chagas, Leish.,
NPIMR- Filariasis
STI- Malaria, Leish. Afr tryps., Chagas, LSHTM -
Malaria, Chagas, Leish.
Secondary Repeat in vitro in vivo assays Lead
ident.
NPIMR- Filariasis
LSHTM/TBRI - Schisto.
LMPH- Malaria, Leish., Tryps.
Follow-on Studies Lead Optim.
Medicinal Chemistry and PK/metabolism networks
18Summary of Compound Supply in Past 8months
(parasite testing)
- Pfizer 12,000 compds
- Chemtura 900 compds
- Serono 100 compds
- ChemRoutes 100 compds
- Other companies 100 compds
- Academia gt 200 compds
- Chem Network/HTS gt 100 compds
- Compound storage, handling and data management
are essential
19Medicinal Chemistry Network
20Definitions 'hit', 'lead', 'development
candidate'
- 'Hit' - compound with selective in vitro activity
(usually IC501uM) against target whole organism
and/or protein. - 'Lead' - compound with drug characteristics, and
efficacious in disease animal model with no overt
toxicity. - Development candidate optimized lead compound
with in vitro and in vivo activity equivalent or
better than drug standards, acceptable
pharmacokinetic and toxicity profile, amenable to
cost-effective scale-up
21HTS Target-based Approach
- Analysis of parasite genomes identifies molecular
targets - drives rational identification of putative
inhibitors - Allows access to greater numbers of compounds
- HTS against proteins should be seen as
supplementary to whole parasite testing - So far few success stories in anti-infectives
- HTS approach would not have identified many of
current anti-parasitic drugs - e.g. artemisinins
22HTS Collaborations
- WEHI and TDR 3 screens completed
- Tcruzi Trypanothione Reductase, Tbrucei Farnesyl
pyrophosphate synthase, Pf Pyrophosphokinase - Some chem PK for early lead optimization
- Serono and TDR 3 screens completed other
ongoing - Pf Serine protease Lm Cysteine peptidase
(completed) - Pf CDPK, Pf Tbr GSK3 (ongoing)
- 2 DEC scientists trained 2 others being trained
- Paucity of hits from HTS showing whole cell
activity, exemplifies high attrition rate in the
molecular target paradigm -
23Creation of Drug Target Portfolio Rational
- Listing of putative drug targets from human
protozoan helminth parasites has not been
carried out systematically - Facilitate prioritization of targets for HTS
campaigns - Generate info. on validation status of the
targets, assay availability amenability for HTS
campaign -
- Aid various agencies in funding decisions
Open Source Database
24Drug Target Portfolio Network
- UW Seattle, USA (Wes Van Voorhis)
- U. Penn, USA (David Roos)
- Sanger Center, UK (Matt Berriman)
- WEHI, Australia (Stuart Raph)
- Biotech Institute, Argentina (Fernan Aguero)
- Additional Resource from
- Pfizer (Andrew Hopkins/Mike Witty)
- Inpharmatica (John Overington)
- UCSF (Andrej Sali)
25Helminth Initiative a Gap
Grand Challenges
Helminth Initiative?
New knowledge / discoveries
New and improved tools
New and improved tools
New and improved tools
New and improved interventions
New and improved strategies
DNDi
NIH, Trust, Research councils, etc
26TDR Drug Discovery Portfolio
Lead ID (Vitro/vivo test, Med. Chem, PK)
Preclinical Development
Lead Opt.
HTS
Genomics
Malaria 4 lead series
HDAC Inhibition Malaria
WEHI 3 targets
Portfolio of drug targets and database being
developed
TDR 22093 With MMV
African Tryps 1 lead series
Leishmaniasis 1 lead series
Cyclodepsipeptides
Helminths 1 lead series
Pfizer collaboration
Serono Collaboration
Helminth Initiative
27Conclusions
- "We lack a robust pipeline of products in
discovery and development to deliver drugs that
meet required target product profiles for
tropical diseases" - "A better coordination mechanism that encourages
sharing of information and exchange to maximize
stakeholders resources are needed" the network
approach is attractive
Nwaka and Hudson 2006