COLLABORATIVE APPROACHES TO THE
DISCOVERY AND DEVELOPMENT OF NEW
ANTICANCER DRUGS
Dr Rob Williams, Chief Drug Development Scientist (DDO),
Cancer Research UK
AcademiaPharma Development Partnerships Summit.
20th November 2013, London
Today’s Talk
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Current landscape for R&D of new medicines
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Industry-Academia collaborations
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Delivering on the promise of stratified
medicine
Cancer – Some Sobering Thoughts
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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 2013.
It is predicted that the global incidence of cancer will
double by 2030.
What is Cancer?
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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
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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
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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) 711-715, 2004.
Pharma and Biotech Focus on Academic Collaborations
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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
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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)
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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
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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).
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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.
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Our Start-up Companies
CRT has been involved in the formation and development of more than 24 start-ups
Company
Acublate Limited
BliNK Therapeutics
Summary
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.
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 2006.
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
Strategic Alliance: Case study
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
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Focusing on relevant projects selected from CR-UK
funded research programs
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Drug discovery carried out at CRT-DL in London and
Cambridge and AstraZeneca cancer centre near Manchester
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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
Advancing Discoveries to Beat Cancer
Academic Consortia Models
Deubiquitinating enzymes (DUBS) – alliance with
Forma signed 2013.
• DNA damage response (DDR) – alliance with Teva
signed 2013.
• Cancer stem cells – seeking partners.
• Senescence – seeking partners.
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Advancing Discoveries to Beat Cancer
Drug Development at Cancer Research UK
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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
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Development function established in 1982.
Over 100 agents taken into early phase trials.
CR-UK Drug Development Infrastructure
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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 2010.
Covering 2000m2 of GMP
production, support and office
space
CR-UK/NHS Experimental Cancer Medicine (ECMC)
Network
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£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
Http://www.Ecmcnetwork.Org.Uk/index.Ht
m.
CR-UK Drug Development Focus
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Develop novel agents where expertise and /or resources to
support further development are lacking.
- Sourced from academic institutes and biotechnology
companies globally.
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Clinical development partnerships (CDP) initiative taking
forward agents shelved by industry.
- Initially targeted at large pharma & biotech.
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‘Sweetspot’ around translation from preclinical development
into FIH phase I/II trials.
Clinical Development Partnerships (CDP): Business Model
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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
COMPANY
DRUG
AstraZeneca
AZD0424
Small molecule
SRC inhibitor
Merck KGaA
Dl-B4
Anti-CD19
antibody
Astex
AT13148
Small molecule
AGC kinase
inhibitor
Centella
KEY CRUK ACTIVITIES
Formulation development & IMP manufacture
FIH clinical trial
IMP manufacture, FIH clinical trial
API process development, formulation
development, IMP manufacture, toxicology,
FIH clinical trial
SN30000
API process development, formulation
Hypoxia activated development, IMP manufacture, toxicology,
cytotoxin
FIH clinical trial
Clinical Development Partnerships (CDP):
Business Deals
COMPANY
DRUG
KEY CRUK ACTIVITIES
Immatics
Biotechnologies
IMA950
Multipeptide vaccine
FIH clinical trial
GSK
GSK1070916A
Small molecule
Aurora Kinase B/C inhibitor
FIH clinical trial
AstraZeneca
AZD3965
Small molecule MCT1 inhibitor
FIH clinical trial
To be announced
To be announced
Preclinical development and FIH trial
To be announced
To be announced
Preclinical development and FIH trial
Tackling Late Stage Attrition
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Paul et al. How to improve R&D productivity: the
pharmaceutical industry’s grand challenge. Nature rev
drug disc. 9: 203-214 (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
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Centre for Medicines Research R&D factbook 2011.
- Significant decline in drugs entering clinical testing.
- 47% less compounds entered phase I in 2010
compared with 2007.
- 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 .
Rapidly emerging resistance to targeted therapy
Before treatment
After 15 weeks
After 23 weeks
A 38-year-old man
with BRAF-mutant
melanoma and
miliary,
subcutaneous
metastatic deposits,
treated with
vemurafenib.
Wagle N et al. JCO 2011;29:3085-3096
©2011 by American Society of Clinical Oncology
Combating Resistance with Drug Combinations –
Historical Successes
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~80% cure rate in hodgkins lymphoma and childhood acute
lymphoblastic leukemia using regimens combining up to 6
chemotherapeutics.
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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
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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
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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
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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.
The CRUK Stratified Medicine Programme Phase I Pilot:
Demonstrating Cancer Gene Testing can be done at Scale
Central data
repository (ECRiC)
Research
infrastructure
Service
delivery
component
Stratified Medicine Programme is Supported by Pharma,
the Government, Diagnostic and IT Companies
CR-UK, Pfizer and AZ fund
the clinical and tech.
hubs
Additional
partners,
£1.4m
TSB and grantees develop
new IT and panel tests
DH CMO & NHS
TSB
grantees,
£5.6m
£5.5m
£5.6m
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
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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
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.........more innovation
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.........more flexibility is required in Pharma R&D
structure and spending
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..........greater openness and collaboration amongst all
stakeholders including industry, academia and
regulators
Are we Making Progress?
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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 (CTD2)
Regulators acknowledging their role as facilitators of
innovation.
Are we Making Progress?
Are we Making Progress?
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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?
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FDA approval of 39 new drugs in 2012 – a 15 year high.
- 20 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.