C OLLABORATIVE A PPROACHES TO THE D ISCOVERY AND D EVELOPMENT OF N EW A NTICANCER D RUGS Dr Rob Williams, Chief Drug Development Scientist (DDO), Cancer Research UK AcademiaPharma Development Partnerships Summit. 20 th November 2013, London

Today’s Talk Current landscape for R&D of new medicines Industry-Academia collaborations Delivering on the promise of stratified medicine

Cancer – Some Sobering Thoughts Getting cancer is one of our greatest fears. Nearly 300,000 new cases of cancer are diagnosed every year in the UK. Someone in the UK is diagnosed with cancer every 2 minutes. More than 1 in 3 of people in the UK will develop cancer. Around 1.3 million EU citizens will die of cancer in It is predicted that the global incidence of cancer will double by 2030.

What is Cancer? A disease characterised by: - Accumulation of somatic mutations caused by physical, viral, radiation or chemical insults. - Uncontrolled cellular proliferation and tumour growth. - Angiogenesis. - Immunoevasion. A disease well controlled by surgery and radiotherapy when localised and caught early. A disease that kills when metastasised and where new treatments are desperately needed.

We are Having to Rethink How We Go About Discovering and Developing New Medicines Most drugs are discovered and developed by pharmaceutical and biotech companies listed on global financial markets. These companies have not been delivering enough return on R&D investment (new medicines reaching the market) to satisfy the demands of the financial markets. Share prices are stagnant or falling (market cap of top ten pharma lower in 2011 than 2001) and research budgets are shrinking. Less venture capital available for ‘discovery-end’ biotech.

Industry Challenges Downward pressure from payers on the price of medicines. Positive health economic assessments increasingly required for reimbursement and drug price setting (e.g. by NICE in the UK). Key patents have expired (the patent cliff). Rising R&D costs. Challenges in the global economy. Unacceptable attrition rates in clinical drug development. Intense focus on new business models to decrease costs and increase efficiency in drug discovery and development Calls for greater collaboration amongst all stakeholders (industry, academia, regulators, payers)

Industry’s Achilles Heel - Attrition in the Clinical Development of New Chemical Entities (NCE’s) Kola and Landis, Nat Rev Drug Disc Vol 3(8) , 2004.

Pharma and Biotech Focus on Academic Collaborations Lack of efficacy is recognised as a key contributor to attrition in clinical development. - Lack of understanding of target biology - Poorly predictive preclinical models - Inappropriate trial designs - One size fits all approach/lack of patient stratification The real in depth understanding of the biological context of potential disease targets resides in academic centres. Clinical & translational research expertise. Opportunity for access to increased biological insight and novel risk sharing deals with the academic sector. 104 new pharma/biotech deals with academia in 2012.

Recent Industry-Academia Drug Discovery Deals Common Features Pharma motivation to access in depth biological and clinical expertise. Emphasis on minimising bureacracy and enabling ‘scientist to scientist’ interactions. Often not pre-competitive deals. Clear emphasis of providing a ROI. Focus on identifying new drug development candidates. Milestone driven programmes.

Cancer Research UK (CR-UK) UK-based, research-focused cancer charity Research spend of £332 million in 2011/12 entirely from public donations. Supports over 4000 academic researchers active in basic, translational and clinical research. Invests in infrastructure (cancer research centres) and training. Provides information on cancer to patients, healthcare professionals and the public. Major influence on uk government wrt policy initiatives on cancer treatment, prevention and scientific research. Wholly own Cancer Research Technology (CRT) – CR-UK’s commercialisation arm.

Drug Discovery in CR-UK/CRT Established activity in CR-UK/CRT. CRT discovery laboratories (Wolfson Institute, London). CR-UK institute programmes - ICR centre for cancer therapeutics (paul workman). - Northern institute for cancer research (herbie newell). - Beatson institute (martin drysdale). - Paterson institiute (donald ogilvie). Historical strategy to license early – no later than mid-lead optimisation. Temodal (temozolamide), a glioma treatment discovered at Aston University. Zytiga (abiraterone acetate), a prostate cancer drug discovered at the ICR.

Advancing Discoveries to Beat Cancer 12 Our Start-up Companies CRT has been involved in the formation and development of more than 24 start-ups CompanySummary Acublate Limited Set up in January 2012 by CRT to develop a next-generation High Intensity Focused Ultrasound (HIFU) surgery device to treat a range of solid tumour types. BliNK Therapeutics Founded in June 2011 by CRT and Paris based Kurma Life Sciences Partners to generate monoclonal antibodies using a novel platform. Discover and develop small molecule drugs based upon chromatin biology. Raised $53m in series C financing. Develop agents that target key cell cycle regulators. Merged with Xcyte Therapeutics Inc. and subsequently raised $45m. Develop drugs based upon DNA damage recognition, signalling and repair. Acquired by AstraZeneca for $210m in MISSION Therapeutics Formed in August 2011, the company will translate cutting-edge cell biology research on DNA repair into drugs that will markedly improve the management of life-threatening diseases, particularly cancer. MISSION Therapeutics has secured £6M in Series-A funding. Develop anti-cancer signal transduction inhibitors. PI 3-kinase programme partnered with Genentech has potential milestones of $230m plus royalties. Acquired by Roche for $160m in 2008.

Advancing Discoveries to Beat Cancer New models for collaboration in drug discovery 3-year, multi-project alliance with AstraZeneca to identify drugs targeting cancer cell metabolism – signed Dec 2009 Target to mid-lead optimisation focus Jointly resourced initiative with a combined team of 30 scientists Focusing on relevant projects selected from CR-UK funded research programs Drug discovery carried out at CRT-DL in London and Cambridge and AstraZeneca cancer centre near Manchester Originating PI’s part of project team AstraZeneca responsible for taking the most promising projects into preclinical and clinical development Deal extended for further 2 years to 2015 Strategic Alliance: Case study

Advancing Discoveries to Beat Cancer Academic Consortia Models Deubiquitinating enzymes (DUBS) – alliance with Forma signed DNA damage response (DDR) – alliance with Teva signed Cancer stem cells – seeking partners. Senescence – seeking partners.

Drug Development at Cancer Research UK Run out of Drug Development Office (DDO) in london. Manages preclinical development and sponsors phase I and II trials of new anticancer agents (currently > 30 active projects). Small molecule therapeutics, antibodies, cell therapies, gene therapies, imaging agents. Global partnerships with academia and industry Development function established in Over 100 agents taken into early phase trials.

CR-UK Drug Development Infrastructure Network of world-class, UK-based experimental cancer medicine centres. In house GMP manufacturing capabilities. Fully integrated clinical operations function delivering ICH-GCP compliant trials. Project management. Quality and regulatory affairs. Non-clinical and medical sciences team.

CR-UK Biotherapeutics Development Unit Process development and manufacture of biological IMPs £18 million investment. Operational Covering 2000m 2 of GMP production, support and office space

CR-UK/NHS Experimental Cancer Medicine (ECMC) Network £35 million (5 years) joint initiative between CRUK and the depts of health for england, scotland, wales and northern ireland. Multidisciplinary scientific and clinical teams dedicated to translating laboratory findings to clinical investigation. Focus on biomarkers and phase I/II trials of new oncology drugs. Eighteen centres across the UK m.

CR-UK Drug Development Focus Develop novel agents where expertise and /or resources to support further development are lacking. - Sourced from academic institutes and biotechnology companies globally. Clinical development partnerships (CDP) initiative taking forward agents shelved by industry. - Initially targeted at large pharma & biotech. ‘Sweetspot’ around translation from preclinical development into FIH phase I/II trials.

Clinical Development Partnerships (CDP): Business Model Joint initiative between CR-UK & CRT targeted at pharma/biotech. Aims to take forward ‘deprioritised’ agents at no upfront cost to partner company. Company grants CR-UK a license to undertake a clinical trial and preclinical development where appropriate. Company retains rights to product, first option to clinical data and opportunity to re-start development. CR-UK receives milestones and royalties if further development is undertaken. Rights transfer to CR-UK (CRT) for further development if option not exercised.

Clinical Development Partnerships (CDP): Business Deals COMPANYDRUGKEY CRUK ACTIVITIES AstraZenecaAZD0424 Small molecule SRC inhibitor Formulation development & IMP manufacture FIH clinical trial Merck KGaADl-B4 Anti-CD19 antibody IMP manufacture, FIH clinical trial AstexAT13148 Small molecule AGC kinase inhibitor API process development, formulation development, IMP manufacture, toxicology, FIH clinical trial CentellaSN30000 Hypoxia activated cytotoxin API process development, formulation development, IMP manufacture, toxicology, FIH clinical trial

Clinical Development Partnerships (CDP): Business Deals COMPANYDRUGKEY CRUK ACTIVITIES Immatics Biotechnologies IMA950 Multipeptide vaccine FIH clinical trial GSKGSK A Small molecule Aurora Kinase B/C inhibitor FIH clinical trial AstraZenecaAZD3965 Small molecule MCT1 inhibitor FIH clinical trial To be announced Preclinical development and FIH trial To be announced Preclinical development and FIH trial

Tackling Late Stage Attrition Paul et al. How to improve R&D productivity: the pharmaceutical industry’s grand challenge. Nature rev drug disc. 9: (2010). - Attrition in late stage development is the most critical determinant of R&D efficiency. - Proposal to redirect resources from late stage clinical development to deliver more early phase studies (ideally phase I POC). - Develop highly networked partnership models for delivery of sufficient numbers of studies.

Current Industry Trends Centre for Medicines Research R&D factbook Significant decline in drugs entering clinical testing. - 47% less compounds entered phase I in 2010 compared with Industry focus on not taking forward candidates with a weak target validation case or undifferentiated candidates. Emphasis on ‘less risky’ candidates with clearly understood and differentiated preclinical profiles. Role for the non-commercial sector in supporting experimental medicine, working with pharma to explore effects of drugs targeting novel mechanisms in the clinic.

Wagle N et al. JCO 2011;29: ©2011 by American Society of Clinical Oncology Before treatmentAfter 15 weeks Rapidly emerging resistance to targeted therapy After 23 weeks A 38-year-old man with BRAF-mutant melanoma and miliary, subcutaneous metastatic deposits, treated with vemurafenib.

Combating Resistance with Drug Combinations – Historical Successes ~80% cure rate in hodgkins lymphoma and childhood acute lymphoblastic leukemia using regimens combining up to 6 chemotherapeutics. Combination anti-retroviral therapy in aids has reduced mortality rates resulting in patients (with access to medicines) living over 20 years post-diagnosis.

CR-UK/ECMC Combination Alliance Initial focus on delivery of early phase combination studies with compounds in active development from a single company. ‘Off critical path’ Investigator designed studies. Local sponsorship of trials via ECMC’s. CR-UK provide single point of co-ordination for peer review, protocol development, safety reviews and grant funding. Studies overseen by a joint steering committee comprised of representatives from CR-UK, ECMCs (investigators) and the company involved. Company pays a modest set up and per patient fee and provides drug. Success milestones upon the continued downstream development and or registration of the combination.

Current Status and Future Plans – First alliance partner AstraZeneca. – In discussion with several pharmaceutical companies for access to novel agents using the same model. – Future interest in: - brokering cross company combination studies. - expanding into preclinical profiling to identify novel combinations.

Combinations Alliance with AstraZeneca – Key Metrics 19 AstraZeneca Compounds Offered 5 Calls Made to the Network 89 Expressions of Interest Received 5 Workshops 11 Application Submissions for peer review 9 Approvals 7 Clinical Studies Open

Stratified Medicines Initiative Targeting medicines to those patients that will benefit clinically and not treating non-responsive patients unnecessarily will be a cornerstone for the future of delivery of healthcare. Cancers having the same anatomical localisation can be driven by different mutations and mechanisms in different people who therefore require different drugs. CR-UK programme launched in 2010 in partnership with the technology strategy board, AZ & Pfizer. Overall aim to develop the UK infrastructure for the future effective delivery of genetic testing for cancer diagnosis and treatment selection.

Service delivery component Research infrastructure Central data repository (ECRiC) The CRUK Stratified Medicine Programme Phase I Pilot: Demonstrating Cancer Gene Testing can be done at Scale

Stratified Medicine Programme is Supported by Pharma, the Government, Diagnostic and IT Companies CR-UK, Pfizer and AZ fund the clinical and tech. hubs TSB and grantees develop new IT and panel tests DH CMO & NHS Additional partners, BMS and Roche provide funding for additional tests and Oracle provide analytics platform

CR-UK Stratified Medicine Programme – Key Metrics (feb 2013) for Phase I Nearly 40,000 gene tests 10,754 patients consented 9,010 samples sent for testing 26 feeder hospitals 8 clinical hubs 6 tumour types 3 technology hubs Phase II with focus on lung cancer to be announced shortly

Comments Spanning a Decade more innovation more flexibility is required in Pharma R&D structure and spending greater openness and collaboration amongst all stakeholders including industry, academia and regulators

Are we Making Progress? Huge range of industry-academia collaborations. High-profile pre-competitive/open source initiatives: - Innovative Medicines Initiative - Critical Path Initiative - Structural Genomics Consortium - International Cancer Genomics Consortium - Cancer Drug Target Disc & Development (CTD 2 ) Regulators acknowledging their role as facilitators of innovation.

Are we Making Progress?

Emergence of monoclonal antibody ‘immune checkpoint modulators’ as drugs able to induce durable regression of multiple tumour types including lung cancers. Prediction that these drugs within 10 years will treat 60% of cancers and earn US$35 billion/year. One of first to emerge (Ipilumumab) was conceived at Berkley, developed by Medarex, acquired by BMS. Preclinical data suggesting similar potential in epigenetics.

Are we Making Progress? FDA approval of 39 new drugs in 2012 – a 15 year high first-in-class drugs - 13 oncology drugs (with patient benefit becoming larger!) - first cycle approval rate 80% UK commitment to life science funding (stratified medicine programme, biocatalyst fund, national biomanufacturing centre, NIHR). Painful for many – but a new, successful ecosystem is evolving that will continue to accelerate the pace of new medicines discovery.