Transcript Neglected Diseases

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
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
Rest of Asia,
Africa and
Australia
8%
Latin America
4%
Japan
11%
Europe
30%
North America
47%
Global Sales 2005 = $566 billion
Disease Burden in DALYs, 2002
Europe
HIV/AIDS
Other
1%
TB
infection
1%
1%
Injuries
15%
Cancer
12%
Neuropsychiatric
21%
Other NC
diseases
24%
Cardiovascular
25%
All infectious diseases 3%
Africa
Injuries
12%
Other NC
7%
Blindness
3%
HIV/AIDS
25%
Cardiovascular
4%
Neuropsychiatric
7%
Other
infection
22%
Malaria
16%
TB
4%
All infectious diseases 67%
Source: Gottret and Schieber (2006) Health Systems Revisited (World Bank)
Parasitic Disease Burden *
Disease
Health burden Deaths
(millions)
(million DALYs)a
(per annum)
HIV / AIDSb
33
89
1.1 million
Tuberculosis
2,000
36
1.6 million
275
42
1.1 million
Sleeping sickness
Chagas' disease
Leishmaniasis
0.4
18
12
1.6
0.6
2.0
50,000
13,000
59,000
Schistosomiasis
Onchocerciasis
Filariasis
200
18
120
1.8
1.0
5.6
15,000
0
0
VIRAL
BACTERIAL
Malariac
PROTOZOAL
HELMINTHIC
Infected
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
Neglected Kinetoplastid Diseases
Sleeping sickness
Visceral
leishmaniasis
Chagas’ Disease
Cutaneous
leishmaniasis
Mucocutaneous
leishmaniasis
Human African Trypanosomiasis
1ary Chancre
Early haemolymphatic stage
Late CNS stage
Trypanosoma b. rhodesiense (acute form)
Trypanosoma b. gambiense (chronic form)
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
The 10-90 Gap
Global Health Spending
(US$ 351 billion)
Global Disease Burden
(DALYs 1.5 billion)
Low (2%) and middle (10%)
income countries
Low and middle
income countries
High income
countries
88%
US$3,039 per person
per year
US$30-82 per person
per year
High income
countries
Source: Gottret and Schieber (2006) Health Systems Revisited (World Bank)
Drug Discovery – Timelines and Attrition
Discovery >30 yrs
Molecular or
Target
Cellular Target
Assay
Preclinical ~6 years
Screen
Hit
Lead
Clinical ~6-8 years
Clinical
Candidate
Phase 1
~250 Projects +
US$ 800m
Phase 2
Phase 3
Clinical
Candidate
Pre-clinical
Assessment
Delivery ~5-10 yrs
Approval
Phase 4
New
Drug
1
Drug
Drug Discovery – the Gaps
Basic research findings
do not enter discovery
pipeline
Target
Product
Profile
Discovery
New or existing
drugs do not
reach patients
ClinicalLead
Preclinical
Gap 1
Gap 2
Delivery
Gap 3
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.
New
Drug
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
Drug Discovery – Bridging the Gaps
Academic Drug Discovery
Groups
University of Dundee
WEHI / HMS / UoT / UCSF
Target
Product
Profile
Discovery
Governments / NGOs
WHO / MSF / GATB
MMV / RBM
ClinicalLead
Preclinical
Gap 1
Gap 2
Delivery
Gap 3
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.
New
Drug
Patient
Pathogen
Genome
Drug Discovery at
Dundee – Excellence
in science with best
industry practice
Metabolome
Parasitology
Targets
Bioinformatics
Compounds
Biochemistry
N
N
Structural biology
N
Cl
Screens
S
Medicinal chemistry
Pharmacology
& Toxicology
Goal: At least one preclinical
candidate in 5 years
Infrastructural Resources
Sir James Black Centre - £19.5 m
(2005)
Wellcome Trust Biocentre - £13.5 m
(1997)
Financial Resources
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
Drug
Discovery
Unit
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)
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)
Strategy to Fill Early Discovery (Gap 1)
Target Prioritisation
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●
●
Validation
Drugability
Assay Feasibility
Toxicity
Resistance potential
Structural Information
Compound Sets
DMPK
in vivo models
MTS/HTS Robotics
in vitro models
Data Management
Structural Biology
Medicinal & Computational Chemistry
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
Current Drugs for Human African Trypanosomiasis
Suramin
Parenteral administration (i.v.)
Inactive in all late stage disease
Prolonged 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 cases
Toxicity (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
Eflornithine plus
nifurtimox
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)
Frequent toxicity (anorexia, nausea, vomiting, peripheral neuropathy, skin
reactions, CNS effects)
Future availability and cost (Bayer)
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
Target Product Profile for Human
African 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 coinfections
 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)
Selection of Quality Targets
Kinetoplast
Nucleus
2K2N
1K1N
2K1N
Metabolome
VSG & GPI Anchor
Cell Cycle
Membrane targeting
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
●
●
●
Target Assessment Criteria
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 nonessential
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
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)
Structural
Information
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)
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-Myristoyltransferase
Kinase 1
PLK
Chemical target
validation 4
PK4
KPST Series 01
GSK 07
Kinase 2
RNA Ligase
GSK3
Kinase 3
Pyridoxal kinase
PK50
Chemical target
validation 1
Chemical target
validation 2
In collaboration with DNDi/Scynexis
In collaboration with BioPharma companies
KPST: Kinase focussed set phenotypic screening vs.
T. brucei
KPSM: Kinase focussed set phenotypic screening vs.
P. falciparum
KPSM
Trypanothione
synthetase
UDP-Glc-4’epimerase
PTR1/DHFR
UDP-GlcNAc
diphosphorylase
CRK3
PS-Q series
Trypanothione
reductase
Studies on hold
and project
returned to
originating lab to
address no go
issues
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-Myristoyltransferase
Kinase
PLK
Chemical target
validation
PK4
KPST Series 01
GSK 07
Kinase
RNA Ligase
GSK3
Kinase
Pyridoxal kinase
PK50
Chemical target
validation
Replication licensing
inhibitors
KPSM
Chemical target
validation
Phosphatase inhibitors
SUMO repressor RNAi
screen
Trypanothione
synthetase
NFκB repressor
RNAi screen
Fungal targets 2,3,4
miRNA regulator RNAi
screen
Nonsense mutation read through agents
Viral protease
Stem cell modulation agents
Numerous campaigns
In collaboration with DNDi/Scynexis
In collaboration with BioPharma companies
KPST: Kinase focussed set phenotypic screening vs.
T. brucei
KPSM: Kinase focussed set phenotypic screening vs.
P. falciparum
Other disease indications
UDP-Glc-4’epimerase
PTR1/DHFR
UDP-GlcNAc
diphosphorylase
CRK3
PS-Q series
Trypanothione
reductase
Fungal Target 1
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
Breaking the Cycle of Parasitic Disease
Vector
Drugs
Chemical
Physical
Biological
Host
Parasite
Control
Tools
Vaccines
Diagnostics
Health Education, Training & Capacity Strengthening
Breaking the Cycle of Poverty and Disease
Disease
transmission
Poor environmental
quality
Poverty
Bad housing
Overcrowding
Indoor smoke pollution
Poor sanitation
Unsafe water
Malnutrition
Inadequate health care
Bad housing
Overcrowding
Indoor smoke pollution
Poor sanitation
Unsafe water
Malnutrition
Inadequate health care
Disease
Social &
economic
impact
Morbidity
&
mortality
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