Neglected Diseases – Mission impossible?

1. Neglected Diseases – Mission impossible? Alan Fairlamb Co-director Drug Discovery Unit, University of Dundee http://www.drugdiscovery.dundee.ac.uk/ Wake up your Governemnt Too many have sleeping sickness

2. Neglected Diseases: Definition • High prevalence: • diseases of developing nations, i.e. most tropical diseases • Low prevalence: • diseases of developed nations, i.e. orphan diseases • Neither is economically viable for pharmaceutical companies to engage in discovery and development of new drugs, vaccines and diagnostics One child dies every 30 seconds from malaria Global Sales 2005 = $566 billion

3. Disease Burden in DALYs, 2002 Europe Africa All infectious diseases 3% All infectious diseases 67% Source: Gottret and Schieber (2006) Health Systems Revisited (World Bank)

4. 33 89 2,000 36 275 42 0.4 18 1.6 12 0.6 2.0 200 18 1.8 120 1.0 5.6 Parasitic Disease Burden * Health burden (million DALYs)a Infected (millions) Deaths (per annum) Disease HIV / AIDSb 1.1 million VIRAL BACTERIAL Tuberculosis 1.6 million 1.1 million PROTOZOAL Malariac Sleeping sickness 50,000 Chagas' disease 13,000 Leishmaniasis 59,000 HELMINTHIC Schistosomiasis 15,000 Onchocerciasis 0 Filariasis 0 a Disability-adjusted life years lost to the community, c.f. War = 20 million DALYs b 80% of all deaths in Africa c 90% of all deaths in Africa * World Health Report estimates, 2002

5. Neglected Kinetoplastid Diseases Sleeping sickness Chagas’ Disease Visceral leishmaniasis Cutaneous leishmaniasis Mucocutaneous leishmaniasis

6. Human African Trypanosomiasis 1ary Chancre Early haemolymphatic stage Late CNS stage Trypanosoma b. rhodesiense (acute form) Trypanosoma b. gambiense (chronic form)

7. New Antiparasitic Drugs – past 25 years 16 new drugs for all neglected tropical diseases (1% of total) Only 4/16 are entirely suitable for DEC use Many drugs developed by “piggy-backing” (e.g. ivermectin) Most drugs not developed for resource poor settings (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

8. The 10-90 Gap Global Health Spending (US$ 351 billion) Global Disease Burden (DALYs 1.5 billion) Source: Gottret and Schieber (2006) Health Systems Revisited (World Bank)

9. Drug Discovery – Timelines and Attrition Discovery >30 yrs Preclinical ~6 years Clinical Candidate Molecular or Cellular Target Pre-clinicalAssessment Hit Lead Target Assay Screen Clinical ~6-8 years Delivery ~5-10 yrs New Drug Clinical Candidate Phase 4 Approval Phase 1 Phase 2 Phase 3 ~250 Projects + US$ 800m 1 Drug

10. Drug Discovery – the Gaps Basic research findings do not enter discovery pipeline New or existing drugs do not reach patients TargetProductProfile New Drug Delivery Lead Discovery Preclinical Clinical Gap 3 Gap 1 Gap 2 Validated candidate drugs do not enter into clinical development 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.

11. Overcoming Gaps & Obstacles • Maximise success, minimise risk (“de-risking”) • good targets, good leads • Piggy-back strategy • veterinary, antifungal, anticancer drugs • 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

12. Drug Discovery – Bridging the Gaps Academic Drug Discovery Groups University of Dundee WEHI / HMS / UoT / UCSF Governments / NGOs WHO / MSF / GATB MMV / RBM TargetProductProfile New Drug Delivery Lead Discovery Preclinical Clinical Gap 3 Gap 1 Gap 2 Product Development PPPs MMV, TB Alliance, iOWH, DNDi, TDR 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.

13. Drug Discovery at Dundee – Excellence in science with best industry practice Patient Pathogen Genome Metabolome Parasitology Targets Bioinformatics Compounds Biochemistry Structural biology Screens Medicinal chemistry Pharmacology & Toxicology Goal: At least one preclinical candidate in 5 years

14. Infrastructural Resources Sir James Black Centre - £19.5 m (2005) Wellcome Trust Biocentre - £13.5 m (1997)

15. Drug Discovery Unit Financial Resources The Wellcome Trust £8.1 m The Wolfson Foundation £2 m DNDi £0.3 m (+$3 m) MMV £0.1 m Drugs for neglected diseases SFC £1.4 m University of Dundee £2.5m Commercialisation of basic research, training in biotech and job creation European Regional Development Fund £1.4 m (Total funding over 5 yrs for translational research: £15.6 m)

16. Strategy 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 • Strong management structure • Clear timelines • Clear decision points • Balanced portfolio of target-based, structure-based and cell-based approaches • Quality validated targets • Innovation versus clinical precedence • Assessment entry criteria • Quality screening collection • Drug-like compounds (LOPAC, Prestwick, etc) • Focussed collections (kinases, HSPs, etc)

17. Strategy to Fill Early Discovery (Gap 1) ● ● ● Target Prioritisation Validation Drugability Assay Feasibility Toxicity Resistance potential Structural Information Compound Sets MTS/HTS Robotics in vitro models in vivo models DMPK Data Management Structural Biology Medicinal & Computational Chemistry

18. Unmet Medical Need – Human African 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

19. Current Drugs for Human African Trypanosomiasis

20. Feasibility & Goal for Human African Trypanosomiasis • Feasibility: • 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

21. Target Product Profile for Human African Trypanosomiasis

22. Selection of Quality Targets Kinetoplast Nucleus 2K2N 1K1N 2K1N Metabolome Cell Cycle Membrane targeting VSG & GPI Anchor

23. ● ● ● Quality Target Assessment – Traffic Light System • Red • Insufficient evidence or inadequate resource • Amber • Partial evidence or partial resource • Green • Adequate evidence and adequate resource  Stop • Genetic evidence the target is not essential for growth or survival in the mammalian host • Chemical evidence the target is not druggable, chemical tractability issues, ADME-Tox issues or failure to progress

24. Target Assessment Criteria

25. Quality Compounds General Screening Set • ~60,000 compounds from 3.8 million commercially available (no IP issues) • ‘Lead-like’ collection (“rule of 4”) • Maximum cluster diversity without overrepresentation • Chemical tractability • Few unwanted toxicophoric groups • Quality control • 0.32% showed indications of aqueous insolubility at 30 M • 96% of compounds > 90% purity • Identity (100% of 1% analysed) Focussed protein kinase inhibitor set • Compiled using a template approach • 3,855 compounds representing 146 templates Prestwick Library & Sigma LOPAC (> 1200 off-patent drugs) Fragment Set(under construction)

26. DDU Portfolio for HAT January 2009 Target assessment Assay Development Hit Discovery Hit Validation Hits to Leads Lead Optimization Sugar dehydrogenase De-N-acetylase Chemical target validation 3 KPST Phenotypic screening hit N-Myristoyl- transferase Kinase 1 PLK Chemical target validation 4 PK4 KPST Series 01 GSK 07 Kinase 2 RNA Ligase GSK3 Kinase 3 Pyridoxal kinase PK50 KPSM Chemical target validation 1 Chemical target validation 2 Trypanothione synthetase Studies on hold and project returned to originating lab to address no go issues In collaboration with DNDi/Scynexis UDP-Glc-4’- epimerase PTR1/DHFR In collaboration with BioPharma companies CRK3 UDP-GlcNAc diphosphorylase KPST: Kinase focussed set phenotypic screening vs. T. brucei Trypanothione reductase PS-Q series KPSM: Kinase focussed set phenotypic screening vs. P. falciparum

27. DDU Portfolio January 2009 Target assessment Assay Development Hit Discovery Hit Validation Hits to Leads Lead Optimization Sugar dehydrogenase De-N-acetylase Chemical target validation KPST Phenotypic screening hit N-Myristoyl- transferase Kinase PLK Chemical target validation PK4 KPST Series 01 GSK 07 Kinase RNA Ligase GSK3 Kinase Pyridoxal kinase PK50 KPSM Chemical target validation Replication licensing inhibitors Chemical target validation Phosphatase inhibitors Trypanothione synthetase SUMO repressor RNAi screen NFκB repressor RNAi screen Fungal targets 2,3,4 miRNA regulator RNAi screen Nonsense mutation read through agents Stem cell modulation agents Numerous campaigns Viral protease Other disease indications In collaboration with DNDi/Scynexis UDP-Glc-4’- epimerase PTR1/DHFR In collaboration with BioPharma companies CRK3 UDP-GlcNAc diphosphorylase KPST: Kinase focussed set phenotypic screening vs. T. brucei Trypanothione reductase PS-Q series KPSM: Kinase focussed set phenotypic screening vs. P. falciparum Fungal Target 1

28. Benefits 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

29. Breaking the Cycle of Parasitic Disease Vector Host Parasite Drugs Chemical Control Tools Physical Vaccines Biological Diagnostics Health Education, Training & Capacity Strengthening

30. Breaking the Cycle of Poverty and Disease Bad housing Overcrowding Indoor smoke pollution Poor sanitation Unsafe water Malnutrition Inadequate health care Disease transmission Poor environmental quality Disease Poverty Bad housing Overcrowding Indoor smoke pollution Poor sanitation Unsafe water Malnutrition Inadequate health care Social & economic impact Morbidity & mortality

31. Conclusion Complex problems require complex solutions Cooperation 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.” • Margaret Chan, Director General, WHO