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

http://www.drugdiscovery.dundee.ac.uk/http://www.drugdiscovery.dundee.ac.uk/

Neglected Diseases: DefinitionNeglected 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

Latin America4%

Rest of Asia, Africa and Australia

8%

Japan11%

North America47%

Europe30%

One child dies every 30 seconds from malaria

Global Sales 2005 = $566 billion

Blindness3%

Injuries12%

Cardio-vascular

4%

Other infection

22%TB 4%

HIV/AIDS25%

Malaria16%

Neuro-psychiatric

7%

Other NC7%

Cancer12%

Neuro-

psychiatric21%

Injuries15%

Other infection

1%

HIV/AIDS1%

TB1%

Cardio-vascular

25%

Other NC diseases

24%

Europe Africa

Disease Burden in DALYs, 2002Disease Burden in DALYs, 2002

All infectious diseases 3% All infectious diseases 67%

Source: Gottret and Schieber (2006) Health Systems Revisited (World Bank)

DiseaseInfected(millions)

Health burden(million DALYs)a

VIRAL HIV / AIDSb

1.6 millionBACTERIAL Tuberculosis

1.1 millionPROTOZOAL Malariac

1.1 million

Sleeping sicknessChagas' disease

Leishmaniasis

HELMINTHIC SchistosomiasisOnchocerciasis

Filariasis

33

2,000

275

0.41812

20018

120

89

36

42

1.60.62.0

1.81.05.6

Parasitic Disease Burden *

* World Health Report estimates, 2002

b 80% of all deaths in Africa

a Disability-adjusted life years lost to the community, c.f. War = 20 million DALYs

50,000

59,00013,000

15,000

Deaths(per annum)

00

c 90% of all deaths in Africa

Sleeping sickness

Cutaneous leishmaniasis

Mucocutaneous leishmaniasis

Visceral leishmaniasis

Chagas’ Disease

Neglected Kinetoplastid DiseasesNeglected Kinetoplastid Diseases

Human African Trypanosomiasis

Early haemolymphatic stage

Late CNS stage

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.

TargetProductProfile

Overcoming Gaps & ObstaclesOvercoming 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

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

industry practiceindustry practice

Infrastructural ResourcesInfrastructural Resources

Sir James Black Centre - £19.5 m (2005)

Wellcome Trust Biocentre - £13.5 m (1997)

The Wellcome Trust £8.1 m

The Wolfson Foundation £2 m

DNDi £0.3 m (+$3 m)

MMV £0.1 m

SFC £1.4 m

University of Dundee

£2.5m

European Regional Development Fund £1.4 m

Drugs for neglected diseases

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

• 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)

Strategy to Fill Early Discovery (Gap 1)Strategy to Fill Early Discovery (Gap 1)

●

●●

Target Prioritisation

ValidationDrugabilityAssay FeasibilityToxicityResistance potentialStructural Information

in vivo models

Medicinal & Computational ChemistryStructural Biology

in vitro models

Data Management

MTS/HTS RoboticsCompound Sets

DMPK

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)

Melarsoprol

Parenteral administration (slow i.v. infusion)Severe toxicity (death 5%; encephalopathy 10%; pruritus, cardiac failure) High relapse rate (drug resistance?) Future availability and cost (Aventis) Prolonged hospitalisation

Eflornithine

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)

Eflornithine plus nifurtimox

Frequent toxicity (anorexia, nausea, vomiting, peripheral neuropathy, skin reactions, CNS effects)Future availability and cost (Bayer)

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

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

2K1N

2K2N

1K1N

KinetoplastNucleus

Cell Cycle

Membrane targetingVSG & GPI Anchor

Metabolome

Quality Target Assessment –Quality Target Assessment – Traffic Light System 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

●

●●

Target Validation

No / weak evidence target is essential for growth /

survival

Genetic OR chemical evidence target is essential

for growth / survival

Genetic AND chemical evidence target is essential

for growth / survival

Assay Feasibility

No in vitro assay development and/or

significant problem with reagents

In vitro assay exists: development into plate format

possible, but not achieved

Assay ready in plate format. Protein supply assured within

timelines

Druggability

Reaction mechanism unknown. No known inhibitors / substrate

analogues exist

Reaction mechanism known and/or there are known

inhibitors / substrate analogues

Reaction mechanism known. Small molecule inhibitors with

drug-like properties or a clinical precedent in gene

family

Toxicity Issues

Human homologue present. No / little evidence selective inhibition possible

Human homologue present. Some evidence selective

inhibition possible

No known human homologue present or known to be non-

essential

Resistance Potential

Target has multiple gene copies / isoforms in same

species. Subject to escape inhibition

Target has isoforms in same species OR maybe subject to

escape inhibition

Target has no known isoforms in same species.

Not subject to escape inhibition

Structural Information

No structure of target or closely relate homologue

Structure available – no ligand. Opportunity to build a

good model

Ligand-bound structure of target / closely related

homologue at high resolution (<2.3 Å)

Target Assessment CriteriaTarget Assessment Criteria

Quality CompoundsQuality CompoundsGeneral Screening SetGeneral 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)

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

Poverty Disease

Disease transmission

Poor environmental

quality

Social & economic

impact

Morbidity &

mortality

Bad housingOvercrowding

Indoor smoke pollutionPoor sanitationUnsafe waterMalnutrition

Inadequate health care

Bad housingOvercrowding

Indoor smoke pollutionPoor sanitationUnsafe waterMalnutrition

Inadequate health care

ConclusionConclusionComplex problems require complex solutionsComplex problems require complex solutions

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.”

• Margaret Chan, Director General, WHO