Transcript Slide 1

Grazie per aver scelto di utilizzare a
scopo didattico questo materiale delle
Guidelines 2011 libra.
Le ricordiamo che questo materiale è di
proprietà dell’autore e fornito come
supporto didattico per uso personale.
The role of academic research in the
development of new drugs
Ian Adcock
National Heart and Lung Institute,
Imperial College London
The future for Academic drug discovery
Overview
• The ‘old way’
• The problems with drug development in
Europe
• A new approach to drug development
• The advantages for Academia
• 2 case studies – severe asthma and COPD
The old way
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Academic groups in isolation
Find new target/novel concept
Test in in vitro, ex vivo and in vivo models
Patent/set up biotech
Obtain funding for small Phase II study
Success/fail – mostly later
Hope that idea taken up by Pharma
A case study – theophylline in COPD
• Observation in clinical trial of low dose
theophylline
• Extensive pre-clinical research in cell lines, primary
cells, murine smoke exposure model
• Many publications
• MRC funded small 30 patient study in patients
• Sub-optimal design due to financial constraints
• Interpretation difficult
• Argenta/Galapocos extending studies to inhaled
low dose theophylline/steroid combination
Overview of process
• Academic success as
– Papers, patents etc
• but, long time-delays from concept to results
• Clinical usefulness
– Debatable as study design not optimal
– Old drug difficult to control drug levels
– Placebo often difficult to get
– Novelty to allow new/better targeting
• Off target effects give benefit or mechanism unclear
Bottlenecks with drug development in Europe
• Pre-competitive bottlenecks in the discovery and
development of new medicines identified by IMI
• Need to predict lack of efficacy at the earliest stage.
• This requires the fine tuning of: discovery research, preclinical
development, translational medicine & clinical development
• Iterative exchange between pre-clinical and clinical
developments.
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- Predictive pharmacology and toxicology
- Identification of predictive biomarkers
- Patient studies
- Validation of biomarkers
- Benefit/risk assessment
Collaboration: the advantages for Academia
• Still perform cutting edge research within
framework of drug discovery process identified by
Industry
True collaboration in a
• Input from Industry
– Intellectual
– Analysis
– Financial
• Project management
• Go/No-go decisions easier
pre-competitive
environment:
Replication of data/resources
etc wasteful – IP relates to
white powder not target
Unbiased Biomarkers
for the Prediction
of Respiratory Disease
Outcomes
Innovative Medicines Initiative
call topic:
Understanding Severe Asthma
Clinical phenotypes of asthma
Fixed
Anti-TNF - responsive
obstruction
Xolair - responsive
Exacerbation
Severe
prone
Anti-IL-5 - responsive
Antibiotic
- responsive
Eosinophilic
steroid-responsive
Anti-IL-4 - responsive
Allergic
Bel EH, Curr Opin Pulm Med 2004;10:44-50
Wenzel S, Lancet 2006;386:804-813
Why focus on severe asthma
Facts
– Still poorly understood
– Xolair only new treatment despite €billions for research
Reasons?
– Not a single disease
– Multiple and co-existent mechanisms/phenotypes
– Efficacy of new drugs cannot be predicted from
preclinical models nor from currently defined patient
characteristics
– lack of biomarkers that enable us to effectively track
disease progression or the impact of a novel therapy on
disease in clinical studies
Hypothesis
Biomarker profiles from high-dimensional
molecular, physiological, and clinical data
integrated by an innovative systems biology
approach into distinct handprints
will predict clinical course and therapeutic
efficacy
and identify novel targets for treatment of severe
asthma
Study design
1. Cross-sectional comparative study
2. Longitudinal follow-up during 30 months
3. Iterative preclinical model development (human
ex-vivo, animal in vivo)
4. Proof of concept intervention by randomized
controlled trial
www.ubiopred.eu
U-BIOPRED
The consortium
Biopharma
Companies
9
Multinational
Industry
1
Regulators
1
U-BIOPRED
Patients
& Care
Organisations
6
Academia
20
SME’s
3
U-BIOPRED
Main deliverables
1.
Reaching international consensus on diagnostic criteria
2.
Creating adult/pediatric cohorts and biobanks
3.
Creating novel phenotype ‘handprints’ by combining molecular,
histological, clinical and patient-reported data
4.
Validating such ‘handprints’ in relation to exacerbations and
disease progression
5.
Refining the ‘handprints’ by using preclinical and human
exacerbation models
6.
Predicting efficacy of gold-standard and novel interventions
7.
Refining the diagnostic criteria and phenotypes
8.
Establishing a platform for exchange, eduction and dissemination
‘Systems Medicine’ of Severe Asthma
Patient reported
Clinical
Functional
Cellular
Molecular
Auffray et al. Thorax 2010
Ethos U-BIOPRED
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Spirit
- Scientific friendship
- Sincerity and transparency
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Paradigm
- Including the new
- Preserving the best
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Consortium
- Expertise
- Excellence
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Each partner
- Input
- Responsibility
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Delivery
- Accuracy
- Reliability
www.ubiopred.eu
MRC/ABPI Inflammation and Immunology Initiative –
COPD - Moving Research To The Clinic
• For this initiative to succeed the focus needs to be
consortium-centric rather than investigator/company-centric.
• The Consortium aims to make this initiative a “game changer”
for COPD and make COPD therapeutically tractable.
• Envisage cross WP industrial style “science” projects for
further funding that will test clear hypotheses.
• Projects are a partnership between Academic and Industry
members - set objectives, design experiments and propose
go/no go decisions.
• The Consortium should serve as a platform for future funding.
WP1 – COPD Phenotyping
Applicants:
Singh – Manchester
Brightling - Leicester
ABPI Lead: Tal-Singer - GSK
• Establishment of a WP management committee, an ethico-legal
& safety board.
• Development of a data sharing and knowledge management
platform
• Follow-up assessments to validate and assess the reproducibility
of candidate biomarkers of exacerbation sub-phenotypes,
muscle dysfunction and sub-phenotypes of disease progression
such as ‘emphysema’ versus ‘small airway disease’.
• Bio-statistical analysis to determine the replication of candidates
from aim (iii) and modelling of patient sub-phenotypes.
• Bio-resource: collection of patient samples to support
phenotyping effort of WP1 and mechanistic studies in the other
WPs.
WP2 - Mechanisms, impact and therapeutic targeting of microbial and
viral colonisation in COPD
Applicants: Barnes, Donnelly: Imperial College
Wedzicha, Donaldson: UCL
Whyte, Dockrell: Sheffield
Stockley: Birmingham
ABPI Lead: Yeadon - Pfizer
Workstream 1: How does bacterial and viral colonisation relate to abnormal
innate and adaptive immunity and to clinical outcomes?
1.1. Longitudinal study (3 yr) of epidemiology of bacterial colonisation and relationship
to exacerbation, disease phenotype and progression
1.2. Phenotyping of innate and adaptive immune profile in BAL fluid (with WP3)
1.3. Relationship of immune profile to bacterial and viral colonisation (WP3)
1.4. Relationship of immune profile to clinical phenotype
1.5. Measurement of bacterial and viral clearance by inflammatory cells (WP3)
Workstream 2: Elucidation of the mechanisms of defective innate immune
responses and identification of novel therapeutic targets.
2.1. Elucidation of mechanisms of defective macrophage phagocytosis of bacteria and
apoptotic cells in COPD
2.2. Elucidation of mechanisms of defective neutrophil phagocytosis function in COPD
2.3. Normalisation of defective innate responses in both macrophages and neutrophils
WP3 - Tissue injury and repair
Applicants:
Knox, Jenkins, Johnson: Nottingham
Djukanovic, Davies, Clark: Southampton
Fisher: Newcastle
Chung, Tetley, Kirkham, Adcock: Imperial College
ABPI Lead: Whittaker – Novartis
Workstream 1: Oxidative stress as a driver of airway remodelling.
1.1. Determining the contribution of mitochondrial oxidative stress to airway damage and repair under
conditions of chronic inflammation
1.2. Relationship between oxidative stress and innate immune defence in response to infection or TGFb
stimulation (in part with WP2).
1.3. Differential response of alveolar and bronchial epithelial cells to anti-oxidants
1.4. Localisation of activated key oxidant/anti-oxidant enzymes in airway and lung
1.5. Contribution of mitochondrial oxidative stress on muscle (with WP4)
Workstream 4: Innate immune dysfunction of airway and alveolar epithelial cells.
4.1. Elucidate functional phenotypes of fibroblasts and epithelial cells from COPD patients and controls
4.2. Determine differential innate immunity between alveolar and airways compartments
4.3. Compare with innate and adaptive immune profile in BAL fluid (with WP2)
4.4. Relationship of innate immune profile to bacterial and viral colonisation (WP2)
4.5. Measurement of bacterial and viral clearance by inflammatory cells (WP2)
4.6. Functional phenotype analysis of bronchial and lung tissue explants
2 recommended workstreams have delayed implementation for 18mths
•Oxidative stress and the RAGE/TGFb axis in airway remodelling
•SP-A and SP-D in alveolar injury and repair
WP4 - Reducing the burden of COPD by targeting skeletal
muscle mass and function.
Applicants:
Polkey, Kemp: Imperial
Steiner: Leicester
Greenhoff, Constantin: Nottingham
MacNee: Edinburgh
ABPI Lead: Rubenov - Novartis
1: Regulatory Track
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Examine existing outcome data available within the consortium (e.g. muscle strength, field and laboratory exercise
performance, total and regional muscle mass) and agree which measures should be included in future studies
Identifying the gaps in knowledge that exist relating to these outcomes.
Exploring cross-sectional associations between these and other measures (e.g. lung) from baseline data obtained from
patients recruited to “muscle” cohorts.
2: Pathway identification and validation track
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Take stock of published and unpublished pathway data including data from RBH (n = 98), quantitative gene array data
from Leicester (n = 30, before and after exercise), data from MRC funded resistance training study (Leicester).
Identify areas of collaboration with other WPs (e.g. effect of bacterial colonisation on muscle inflammation).
Start prospective collection of data and samples from patients. Identify how samples should be analysed.
Agree SOPs for obtaining muscle biopsies and for storage and transport to centres where analysis will take place.
Agree candidate pathways going forward and drawing up proposals for hypothesis driven studies for the rest of the WP.
3. Biomarker Track
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Consolidating existing knowledge on blood/urine biomarkers from academia and pharma
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Agreeing biomarker search strategies (eg microRNA, proteomics) that will be used and screen existing samples e.g. (RBH
(n = 100, Leicester samples from AECOPD (n = 300), Leicester resistance training intervention study n = 80).
Agree potential candidate biomarkers for further validation and collect samples.
Academic research in drug development: the future
• Despite funding restrictions – opportunities exist
• Patient cohorts
• Standard characterisation/definitions,
• SOPs etc across EU/USA
• Hypothesis-driven questions are the key
• Collaboration with other Academic Centres/EFPIA members
• Test in key sets/subsets of patients
– Primary cells/tissues from patients with disease
– site of disease
• Predictive animal models of disease
• Replicated across sites
Biomarker development
best performed in collaboration with EFPIA and/or SMEs
MRC/ABPI Inflammation and Immunology Initiative –
COPD - Moving Research To The Clinic
• The MRC/ABPI jointly sponsored a workshop focussed on COPD.
• The event was intended to improve communication and
collaboration between researchers in industry and academia.
Questions
• Have the major needs of the healthcare industry in Immunology
and Inflammation been identified – are there any other issues?
• What opportunities are there for closer interactions between
academia and industry in these areas?
• What are the hurdles to closer alignment between industry and
academia and how can these be addressed?
• What are the next step – what specific actions are there to
exploit new opportunities?
Of mice and men
?
U-BIOPRED
acad*
pat org*
SME*
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MRC/ABPI Inflammation and Immunology Initiative –
COPD - Moving Research To The Clinic
• The MRC Steering group set out a strategy to develop the cohorts first,
harmonise SOPs, scope the availability of tissue etc so that the
consortium is clear as to what is available.
• Evaluation of the cohorts will allow gap analysis and coordination of
the cohorts will go some way to ensuring we get a holistic view of the
disease.
• This would then be used as a resource to test the hypotheses laid out
in WPs 2, 3 and 4.
• The potential of this consortium as a platform for future funding
should not be underestimated.
• The COPD consortium will be an ideal basis for future grant proposals.
New drug development process
12-15 years total
2.5 years
Approval
Regulatory review
Marketing application filed with
regulatory authority
3+ years
2+ years
1 + year
Phase III clinical studies –
extensive clinical studies
Phase II clinical studies – efficacy studies
Phase I clinical studies – pharmacological profile
Regulatory/ethical review committee approval
3+ years
Preclinical laboratory and animal toxicology studies
IRD
NDA
Manufacture
Clinical trials
Process research
Volunteer studies
Toxicology
Patenting
Testing
Screening