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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 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. - 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 Input from Industry – Intellectual – Analysis – Financial Project management Go/No-go decisions easier True collaboration in a 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 Bel EH, Curr Opin Pulm Med 2004;10:44-50 Wenzel S, Lancet 2006;386: Eosinophilic steroid-responsive Exacerbation prone Severe Fixed obstruction Allergic Anti-TNF - responsive Anti-IL-5 - responsive Anti-IL-4 - responsive Xolair - responsive Antibiotic - responsive

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

U-BIOPRED

Regulators 1 Biopharma Companies 9 U-BIOPRED Patients & Care Organisations 6 SME’s 3 Academia 20 Multinational Industry 1 The consortium

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

Auffray et al. Thorax 2010 Patient reported Clinical Functional Cellular Molecular ‘Systems Medicine’ of Severe Asthma

Ethos U-BIOPRED Spirit - Scientific friendship - Sincerity and transparency Paradigm - Including the new - Preserving the best Consortium - Expertise - Excellence Each partner - Input - Responsibility Delivery - Accuracy - Reliability

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 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. Applicants: Singh – Manchester ABPI Lead: Tal-Singer - GSK Brightling - Leicester

WP2 - Mechanisms, impact and therapeutic targeting of microbial and viral colonisation in COPD Applicants: Barnes, Donnelly: Imperial CollegeABPI Lead: Yeadon - Pfizer Wedzicha, Donaldson: UCL Whyte, Dockrell: Sheffield Stockley: Birmingham 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 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 ABPI Lead: Whittaker – Novartis Djukanovic, Davies, Clark: Southampton Fisher: Newcastle Chung, Tetley, Kirkham, Adcock: Imperial College Workstream 1: Oxidative stress as a driver of airway remodelling 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 TGF  stimulation (in part with WP2) 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 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/TGF  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. 1: Regulatory Track – 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 – 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 Consolidating existing knowledge on blood/urine biomarkers from academia and pharma – 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. Applicants: Polkey, Kemp: Imperial ABPI Lead: Rubenov - Novartis Steiner: Leicester Greenhoff, Constantin: Nottingham MacNee: Edinburgh

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 * * * * * * *

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 years total 2.5 years 3+ years 2+ years 1 + year 3+ years Approval Regulatory review Marketing application filed with regulatory authority Phase III clinical studies – extensive clinical studies Phase II clinical studies – efficacy studies Phase I clinical studies – pharmacological profile Regulatory/ethical review committee approval Preclinical laboratory and animal toxicology studies

MARKETING IRD NDA Manufacture Clinical trials Process research Volunteer studies Toxicology Patenting Testing Screening Activity Safety Efficacy Regulatory yr RESEARCH DEVELOPMENT 3 yr Patent