Neglected Diseases – Mission impossible? Wake up your Governemnt Wake up your Governemnt Too many have sleeping sickness Too many have sleeping sickness Alan Fairlamb Co-director Drug Discovery Unit, University of Dundee http://www.drugdiscovery.dundee.ac.uk/ http://www.drugdiscovery.dundee.ac.uk/
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Neglected Diseases – Mission impossible? Wake up your Governemnt Too many have sleeping sickness Alan Fairlamb Co-director Drug Discovery Unit, University.
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Neglected Diseases – Mission impossible?
Wake up your GovernemntWake up your GovernemntToo many have sleeping sicknessToo many have sleeping sickness
Alan Fairlamb
Co-director Drug Discovery Unit, University of Dundee
Trypanosoma b. rhodesiense (acute form)Trypanosoma b. gambiense (chronic form)
1ary Chancre
New Antiparasitic Drugs – past 25 yearsNew Antiparasitic Drugs – past 25 years
16 new drugs for all neglected tropical diseases 16 new drugs for all neglected tropical diseases (1% of total)(1% of total)
Only 4/16 are entirely suitable for DEC useOnly 4/16 are entirely suitable for DEC use
Many drugs developed by “piggy-backing” Many drugs developed by “piggy-backing” (e.g. ivermectin)(e.g. ivermectin)
Most drugs not developed for resource poor settings Most drugs not developed for resource poor settings (e.g. eflornithine)(e.g. eflornithine)
cost (diseases of the poor)efficacy & resistance potential (natural or acquired drug resistance) safety (over counter, non-prescription use)stability (no cold storage)ease of administration (e.g. no hospitalisation; no needles)target population (e.g. pregnant women and children)drug policy (e.g. artemisinin combination therapy)
Source: Moran et al (2005) The New Landscape of Neglected Disease Drug Development
High income
countries
88%
US$3,039 per person
per year
Low (2%) and middle (10%)
income countries
Low and middle
income countries
US$30-82 per person
per year
High income
countries
Global Health Spending(US$ 351 billion)
Global Disease Burden(DALYs 1.5 billion)
Source: Gottret and Schieber (2006) Health Systems Revisited (World Bank)
The 10-90 GapThe 10-90 Gap
Drug Discovery – Timelines and AttritionDrug Discovery – Timelines and Attrition
Pre-clinicalAssessmentLeadHitScreenAssayTarget
Clinical
Candidate
Phase 4ApprovalPhase 3Phase 2Phase 1New
Drug
Preclinical ~6 years
Clinical ~6-8 years Delivery ~5-10 yrs
Discovery >30 yrs
1
Drug
~250 Projects + ~250 Projects + US$ 800m US$ 800m
Clinical
Candidate
Molecular or Cellular Target
Drug Discovery – the GapsDrug Discovery – the Gaps
Lead DeliveryClinicalPreclinicalDiscoveryNew
Drug
Gap 1
Basic research findings do not enter discovery
pipeline
Gap 2 Gap 3
Validated candidate drugs do not enter into clinical
development
New or existing drugs do not reach
patients
Access to Essential Medicines Campaign and the Drugs for Neglected Diseases Working Group. (2001) Fatal imbalance: The crisis in research and development for drugs for neglected diseases.
Public-Private-Partnerships Academic / Pharmaceutical partnerships with upfront funding for
development from Private Foundations, Charities, Governments, WHO Guaranteed returns for pharma
Advance purchase commitments Tax breaks / patent extensions for pharma Priority Review Vouchers for bringing drugs for NTDs to market
accelerated FDA review of any drug for registration Name and shame
bad public relations Lost leader strategy
good public relations access to emerging markets
Lead DeliveryClinicalPreclinicalDiscoveryNew
Drug
Gap 1
Academic Drug Discovery Groups
University of DundeeWEHI / HMS / UoT / UCSF
Gap 2 Gap 3
Product Development PPPs
MMV, TB Alliance, iOWH, DNDi, TDR
Governments / NGOsWHO / MSF / GATB
MMV / RBM
Access to Essential Medicines Campaign and the Drugs for Neglected Diseases Working Group. (2001) Fatal imbalance: The crisis in research and development for drugs for neglected diseases.
TargetProductProfile
Drug Discovery – Bridging the GapsDrug Discovery – Bridging the Gaps
Bioinformatics
Parasitology
Biochemistry
Structural biology
Medicinal chemistry
Goal: At least one preclinical candidate in 5 years
Patient
Pathogen
Genome
Metabolome
Targets
Compounds
Screens
Pharmacology& Toxicology
S
N Cl
N
N
Drug Discovery at Drug Discovery at Dundee – Excellence Dundee – Excellence in science with best in science with best
Commercialisation of basic research, training in biotech and job creation
(Total funding over 5 yrs for translational research: £15.6 m)
Drug Discovery
Unit
Financial ResourcesFinancial Resources
Strategy to Maximise SuccessStrategy to Maximise Success
• Clear, focussed goals – Unmet medical need, feasibility & target product profile
• Adequate resources– Strong science base (internal & external collaborations)– Biotech & pharmaceutical industry expertise – In-house capabilities for all aspect of drug discovery
Unmet Medical Need – Human Unmet Medical Need – Human African TrypanosomiasisAfrican Trypanosomiasis
• ~300,000 cases per annum
• ~50,000 deaths per annum
• Re-emerging epidemic disease
• ~100% fatal if not treated
• Diagnostics inadequate
• Vaccines not possible
• Vector control alone ineffective
• Current drugs are inadequate
Current Drugs for Human African TrypanosomiasisCurrent Drugs for Human African Trypanosomiasis
Suramin
Parenteral administration (i.v.)Inactive in all late stage diseaseProlonged treatment (up to 3 weeks)Toxicity (fatal anaphylaxis ~ 1 in 20,000; skin reactions, reversible renal damage)Future availability and cost (Bayer)
Pentamidine
Parenteral administration (i.m.) Inactive in all late stage disease Inactive in some T.b.rhodesiense casesToxicity (e.g. hypotension, myalgia, sterile gluteal abscess, diabetes)Cost ($ 60-150)
Parenteral administration (i.v. infusions)Inactive against T.b.rhodesiense late stage Prolonged treatment (up to 3 weeks)Reversible toxicity (convulsions; bone marrow suppression; GI symptoms; nerve deafness)Delivery issues (30 kg / patient) and high cost ($750; Aventis)
• T.brucei genome completed• Biology reasonably well understood• Scientific expertise with validated targets• Cytostatic drugs can be effective (eflornithine)• Extracellular life cycle• Simple to assay in culture• Robust, simple in vivo disease models
Goal:• To deliver at least 1 drug candidate for entry into formal
pre-clinical development by March 2011
Feasibility & Goal for Human Feasibility & Goal for Human African TrypanosomiasisAfrican Trypanosomiasis
Broad spectrum – T.b.rhodesiense and T.b.gambiense
Active against known resistance strains, e.g. melarsoprol failure
Safety better than existing drugs (<1% mortality; safe in pregnancy)
Treatment for both early and late stage of disease essential
Parenteral (essential) and Oral formulation (desirable) Few contraindications: drug-drug interactions; HIV or TB co-
infections
Cure in 14 days or less
Affordable – less than current treatment for early stage ($100 – $140)
Low resistance potential
Stable under tropical conditions (> 2 years, 40 C, 75% RH)
Target Product Profile for Human Target Product Profile for Human African TrypanosomiasisAfrican Trypanosomiasis
Selection of Quality TargetsSelection of Quality Targets
DDU Portfolio for HAT January 2009DDU Portfolio for HAT January 2009Hit
DiscoveryHits to Leads
Lead Optimization
Targetassessment
Trypanothione synthetase
N-Myristoyl-transferase
Sugardehydrogenase
Kinase 1
Kinase 2
AssayDevelopment
PLK
Kinase 3
De-N-acetylase
Hit Validation
PK4
PK50
Chemical target validation 4
Chemical target validation 1
Chemical target validation 2
Studies on hold and project returned to
originating lab to address no go
issues
KPST Phenotypic screening hitChemical target
validation 3
RNA Ligase
KPST Series 01
GSK3
GSK 07
In collaboration with DNDi/Scynexis
In collaboration with BioPharma companies
KPST: Kinase focussed set phenotypic screening vs. T. brucei
KPSM
KPSM: Kinase focussed set phenotypic screening vs. P. falciparum
UDP-Glc-4’-epimerase
PTR1/DHFR
CRK3
Trypanothione reductasePS-Q series
UDP-GlcNAc diphosphorylase
Pyridoxal kinase
DDU Portfolio January 2009DDU Portfolio January 2009Hit
DiscoveryHits to Leads
Lead Optimization
Targetassessment
Trypanothione synthetase
N-Myristoyl-transferase
Sugardehydrogenase
Kinase
Kinase
AssayDevelopment
PLK
Kinase
De-N-acetylase
Hit Validation
PK4
PK50
Chemical target validation
Chemical target validation
Chemical target validation
Viral protease
NFκB repressorRNAi screen
Stem cell modulation agentsNumerous campaigns
Nonsense mutation read through agents
KPST Phenotypic screening hit
Fungal targets 2,3,4
Chemical target validation
RNA Ligase
KPST Series 01
GSK3
Phosphatase inhibitors
miRNA regulator RNAi screen
SUMO repressor RNAi screen
GSK 07
In collaboration with DNDi/Scynexis
In collaboration with BioPharma companies
KPST: Kinase focussed set phenotypic screening vs. T. brucei
KPSM
KPSM: Kinase focussed set phenotypic screening vs. P. falciparum
UDP-Glc-4’-epimerase
PTR1/DHFR
CRK3
Trypanothione reductasePS-Q series
Fungal Target 1
UDP-GlcNAc diphosphorylase
Pyridoxal kinase
Replication licensing inhibitors
Other disease indications
Benefits of Our ApproachBenefits of Our Approach• Drug Discovery in an academic setting
– Synergism of academic excellence & industry skills– World leading specialists in organism/target-disease link– Focus on innovative agents, new mechanisms of action– Freedom to address medical need regardless of potential market
size
• Combined with PPP model for clinical development– Best health outcomes-delivering what is needed– More cost effective – Indications of enhanced speed of development– Supported via G8 commitment to increase direct investment into
neglected disease drug development through PPPs
Breaking the Cycle of Parasitic DiseaseBreaking the Cycle of Parasitic Disease
Vector HostParasite
Control Tools
Drugs
Vaccines
Diagnostics
Chemical
Biological
Physical
Health Education, Training & Capacity Strengthening
Breaking the Cycle of Poverty and DiseaseBreaking the Cycle of Poverty and Disease
Cooperation and coordination are keys to successCooperation and coordination are keys to success
• “We have never had such a sophisticated arsenal of technologies for treating disease, yet the gaps in health outcomes keep getting wider. This is unacceptable.”