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Revolutionary Medicine: Opportunities and Challenges in Delivering Molecular Diagnostics
NHS Confederation Annual Conference 2015
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WELCOME
1. Background
2. The Emerging Era of Genomic
Medicine
3. Opportunities & Challenges for
Scaling NGS
Copyright © 2015 NantHealth All Rights Reserved.
Who we are
50%of U.S.
oncologypractices
18countries
10,0
00
clinical trials
6 million
covere
d liv
es
250+connectedhospitals
3 b
illion
transactionsin 2014
Copyright © 2015 NantHealth All Rights Reserved.
• Physician, surgeon, scientist, and inventor
• Founder, CEO and Chairman, Nantworks group companies
• Pioneered revolutionary new diabetes and cancer treatments
• Published over 100 scientific papers, and has over 95 issued patents on groundbreaking advancements spanning myriad fields
• Performed the world’s first encapsulated human islet transplant
• He invented and developed Abraxane, approved for metastatic breast, lung cancer and pancreatic cancer
• Founded VivoRx, American Pharmaceutical Partners and American BioScienceDr Patrick Soon-Shiong, MD
Leadership: Dr Patrick Soon-Shiong
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Has tumour spread?
What molecular subtype?
What dose?
What schedule?
Surgery or Chemotherapy?
What stage?
Pre-operative chemotherapy?
In combination with other drugs?
Address the Information Overload & ‘Big Data’ in Cancer
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Clinical decision-making is becoming more complicated
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BASICSCIENCE
CLINICALSCIENCE
EVALUATIONSCIENCE
What is the patho-
physiology?
What is the
diagnosis and
appropriate
intervention?
Does the
intervention work?
HEALTH CAREDELIVERYSCIENCE
How do we best
deliver the
intervention to
everyone?
NantHealth’s Approach to Leading Change in Healthcare
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The Science of Managing Cancer Care™
Perfect Cancer Care Solution Ecosystem
Pa
tie
nt
Nu
rsin
g
Risk ID & Pop Stratification
Continuous Review, Evaluation & Feedback
Screening
Symptoms
GenomeSequence Annotation
GenerateOrder Sets,
Delivery & Monitoring Schedules
Deliver Treatment:
• Surgery Plans• Medical Plans• Radiotherapy Plans• Chemotherapy
Plans
Deliver Treatment:Nursing Plans and Assessments
Care Management
Palliative EOL
Remission Monitoring
Patient Informed Choice
Patient Self-Care
Man
ag
em
en
t / A
naly
tics
Cli
nic
al
Clinical Trials Management, Health Services and Translational Research & Evaluation
Advanced Molecular
Diagnostics
Genomics
Proteomics
Metabolomics
Stratificationinto OmicCohorts
Initial Therapeutic
Clinical Decision Support
Therapy Segmentation
(Evidence-based Protocols)
MDTs Adapt Treatment
& Care Plans
Care Plan Delivery & Monitoring Schedules
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Revolutionary Medicine –Opportunities and Challenges
• Dr Anthony Williams MRCP FRCPath PhDHon Consultant Clinical Immunologist/Reader in Immunology
• Co-Director Southampton Experimental Cancer Medicine Centre
• (CRUK/NIHR ECMC)
• University Hospital Southampton FT/University of SouthamptonFaculty of Medicine
10
Genomic Medicine Initiatives
2010
2011
2012
2014
2013
11
Precision medicine - P4Medicine
Personalized, Preventative, Predictive, Participatory
1. Molecular and pathway precision in diagnosis2. Precision in treatment with better outcomes3. Treatment closer to disease-causing mechanisms4. Screening and prognostic indicators5. Cost-effective healthcare
UK Cancer network to enable Precision Medicine
18 centres
Harmonising• Clinical Trial Delivery• Stratified Medicine• Industry partnership
> 700 trials > 500 IMPs tested >7,000 cancer patients recruited >700 biomarker studies 100 pharmaceutical partnerships
Service deliverycomponent
Research infrastructure
The Stratified Medicine Programme pilot study combines service delivery and
research components
Central data repository (ECRiC)
Tumour Genes of interest
Colorectal carcinoma KRAS BRAF NRAS PIK3CA TP53 mutation
Breast carcinomaPIK3CA TP53 BRAF PTEN mutation
+ PTEN LOH by microsatellite analysis
Prostate carcinomaPTEN BRAF mutation
TMPRSS2-ERG fusion by FISH (moving to rt-PCR)
+ PTEN LOH by microsatellite analysis
Lung carcinomaEGFR KRAS BRAF mutation
ALK rearrangement by FISH
Ovarian carcinomaTP53 PTEN PIK3CA BRAF mutation
+ PTEN LOH by microsatellite analysis
Malignant melanoma BRAF KIT NRAS PIK3CA mutation
Current gene list and technology
Stratified Medicine
Precision Medicine
Personalised Medicine
Follow on SMP 2 – Lung cancer
Extending the reach of Pathology services
Exome Sequencing
1-2% of Genome (8Gb storage)
Whole Genome Sequencing
400 Gb storage~10,000 songs on ipod)
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Genomics & Proteomics
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Unlock the Power of Proteomics
ASCO 2014 (NH study of 10k tumour and
germline WE and WG representing 5k
patients across 20 tumour types):
• Dance of proteins in the protein pathway
important for targeting of cancer
treatment;
• A cancer patient is largely independent of
anatomical tumour type – cancer as an
infectious disease;
• Supercomputing infrastructure identifying
alterations in DNA, to RNA, to protein
pathway – conclusion that WGS is
useful, but not the whole picture.
• The protein within the genome
develops and spreads cancer. We treat
the protein.
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The Power of Whole Genome Sequencing in Clinical Decision Support
Cancer Gene Mutations are Independent of Anatomical Tumour Types
Cancer Must be Reclassified Based on Molecular Fingerprint Rather than
Anatomical Site
BIG DATA – BIGGER CHALLENGES
21
‘Walk into the light’ Where’s that needle gone’
Biomarkers, Biodiagnostics, Bioinformatics
Robust
Reliable Regulated
Resilient
or
Her2/Breast Cancer BRAF/Skin Cancer
GEL 100K - InfographicGEL 100K Project
24
Rare Disease = 15,000 (45K samples)Current categories:
1. Cardiovascular disorders
2. Dermatological disorders
3. Dysmorphic and congenital abnormality syndromes
4. Endocrine disorders
5. Growth disorders
6. Haematological disorders
7. Hearing and ear disorders
8. Metabolic disorders
9. Neurology and neurodevelopmental disorders
10. Ophthalmological disorders
11. Renal and urinary tract disorders
12. Skeletal, rheumatological, and connective tissue disorders
13. Tumour predisposition syndromes
Cancer = 25,000 (50K samples)Current categories:
1. Lung Cancer
2. Colon Cancer
3. Breast Cancer
4. Prostate Cancer
5. Ovarian cancer
North East and North Cumbria GMC
Newcastle led*
Greater Manchester GMC
Manchester led*
West Midlands GMC
Birmingham led*
East of England GMC
Cambridge led
Oxford GMC
Oxford Led
Wessex GMC
Southampton led *
North Thames GMC
GOSH led
West London GMC
Imperial led
South London GMC
Guys and St Thomas Led*
Genomic Medicine Centres
2015-2017 (Jan 2015)
North West Coast GMC
Liverpool led
South West GMC
Exeter Led
Genomic Medicine Centres
27
Improving Awareness and Education
• Establish retraining opportunities amongst healthcare staff
• Develop a patient and public engagement program to improve understanding of precision medicine
• Work with Universities to establish MSc program in Genomic Medicine
• Develop the capacity to deliver innovations into the NHS
Free On line learning environmentfor healthcare professionals
Continuing Professional development
Adrressing the challenge of large data sets
Developing new professional disciplinesthat integrate computer science, biologyand maths
Health Education England provision of resources
Cancer Immunoediting
Immunotherapy
How many changes are needed to make a cancer cell ?
• Trastuzumab (Herceptin) HER2 protein Her2+ breast, gastric cancer
• Bevacizumab VEGF colon, lung, renal cancer
• Cetuximab EGFR colon, head and neck cancer
• Ipilumumab (anti-CTLA4) met melanoma
• Nivolumab (anti-PD-1) met melanoma, lung, renal cancer
• Rituximab (anti-CD20) NHL
• Alemtuzumab (anti-CD52) CLL
• Ofatumumab (anti-CD20) CLL
• Brentuximab Vedotin (anti-CD30) Hodgkin’s lymphoma
• Gemtuzumab ozogamycin (anti-CD33) AML
• 90Y-Ibrutumomab tiuxetan (anti-CD20) NHL
• 131I-Tositumomab (anti-CD20) NHL
• Trastuzumab emtansine TDM-1 HER2 protein Her2+ breast cancer
• Lenalidamide pro-apoptotic haematological malignancies
• Ibrutinib BTK inhibitor haematological malignancies
• Sipiluceucil-T vaccine prostate cancer
• Denileukin diftitox CD25 T-cell lymphomas
Immunotherapeutic Agents
Nature Reviews | Cancer
Pretreatment Post-treatment
Dermatitis
Colitis
Colitis
Hepatitis
PD1-pathway blockade71. Finally, although the major
role of the PD1 pathway is in limiting immune effector
responses in tissues (and tumours), it can also shift the
balance from T cell activation to tolerance at the early
stages of T cell responses to antigens within secondary
lymphoid tissues (that is, at a similar stage as CTLA4).
Taken together, these findings imply a complex set of
mechanisms of action for PD1-pathway blockade.
Regulation of expression of PD1 and its ligands in
tumours: constitutive versus adaptive immune resist-
ance. PD1 is expressed on a large proportion of tumour-
infiltrating lymphocytes (TILs) from many different
tumour types72,73. Some of the enhanced PD1 expres-
sion among CD4+ TILs reflects a generally high level
of PD1 expression on TReg
cells, which, as noted above,
can represent a large proportion of intratumoral CD4+
T cells. Increased PD1 expression on CD8+ TILs may
either reflect an anergic or exhausted state, as has been
suggested by decreased cytokine production by PD1+
compared with PD1– TILs from melanomas73.
Just as PD1 is highly expressed on TILs from many
cancers, the PD1 ligands are commonly upregulated
on the tumour cell surface from many different human
tumours2,56. On cells from solid tumours, the major
PD1 ligand that is expressed is PDL1. Forced expres-
sion of PDL1 on mouse tumour cells inhibits local
antitumour T cell-mediated responses56,74,75. Indeed,
this combination of findings provides the basis for
PD1-pathway blockade to enhance anti tumour effec-
tor functions in the tumour microenvironment.
Immunohistochemistry (IHC) techniques and flow
cytometry-based analyses of surface expression have
shown that the selective upregulation of PD1 ligands
in various types of human tumour is hetero geneous
at a number of levels58. Expression patterns of PD1
ligands may be crucial for determining the suitabil-
ity of therapeutic blockade of this pathway because
its primary role in cancer is thought to be immune
inhibition within the tumour microenvironment and
because PD1 only inhibits lymphocyte function when
it is engaged by its ligands, PDL1 and PDL2.
Figure 2 | Clinical responses and immune-mediated toxicities on antibody blockade of the CTLA4-mediated
immune checkpoint. Depicted on the left of the figure are examples of regressions of lung (top two panels) and brain
(lower panel) metastases in a patient with melanoma who was treated with the cytotoxic T-lymphocyte-associated
As shown on the right of the figure, common tissues affected by immune-related toxicities from treatment with
anti-CTLA4 therapy include the skin (dermatitis) and the colon (colitis). Tissues that do not undergo such rapid
regeneration as the skin and colon, such as lung and liver and the pituitary and thyroid glands, are less frequently
affected. Immune toxicities from anti-CTLA4 therapy are usually successfully mitigated by treatment with systemic
steroids and tumour necrosis factor (TNF) blockers when systemic steroids are not effective. Ongoing tumour responses
typically continue even after a course of steroids. Figure is reproduced, with permission, from REF. 39 © National
Academy of Sciences, USA.
REVIEWS
NATURE REVIEWS | CANCER VOLUM E 12 | APRIL 2012 | 257
FOCUS ON t UmOUR ImmUNOl Og y & ImmUNOt h ERa py
© 2012 Macmillan Publishers Limited. All rights reserved
Objective response rate 17% in heavily pretreated patients with advanced lung cancer
Median duration of response 74 weeks (1.4 years)
Median Overall Survival 10 months
1-year Survival 42%;
2-year Survival 24%
2% Severe immune-related toxicity with Pneumonitis
3 treatment-related deaths (2%)
35
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Improved Survival for Melanoma
(months)
9.1 10.1 11.2 16.8 39.7
36.3% 45.6% 47.3% 63% 85%
17.9% 23.5% 28.5% 48% 79%
10.3% 10.9% 15.2% 32% 53%
1 Robert, Thomas et al. NEJM, 2011
2 Hodi, O’Day et al. NEJM, 2010
3 Topalian et al. NEJM, 2012; Topalian et al, JCO, 2014
4 Wolchok et al. NEJM, 2013; Sznol et al. ASCO Abstract, 2014
38
Challenges and Opportunities
Academic Health Science Networks
University Hospital Southampton NHS FT
University of Southampton
Southampton Centre for Biomedical research
£25MCancer Immunology Centre
www.southampton.ac.uk/youreitOpen 2017
NIHR/Southampton Nutrition
Biomedical Research Centre
NIHR/Southampton Respiratory
Biomedical Research Centre
NIHR/Cancer Research UK
Experimental Cancer Medicine Centre
Genomics England/NHSE
University Hospital Southampton University of Southampton
Partnership and Collaboration
NIHR/Wellcome Trust
Clinical Research Facility
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17
Delivering Precision Oncogenomics and Cancer Care Transformation in the Era of Molecular Medicine - from Genomics to Actionable Information across the Care
Continuum
Personalised – Coordinated – Proactive
The Business Proposition
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The NantHealthValue Proposition
The Evidence base:
1. Forastiere et al, Univ of Pennsylvania & Johns Hopkins University ‘cost of care
deviations in oncology care’, June 2013
2. GEHA
3. Wellpoint Study, May 2014
4. Cancer Research UK, ‘Saving Lives, averting costs’, Sept 2014
5. Bosanquet & Evans, ‘Sustaining Universal care in the UK’, Sept 2014
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The NantHealthValue Proposition – the opportunity
Dr Arlene Forastiere et al, ‘The cost per patient of deviations from evidence-based standards of oncology care’, 3 June 2014
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The NantHealthValue Proposition – the response 1
• Government Employees Hospital Association (GEHA)
•
•
•
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The NantHealthValue Proposition – the response 2
• Wellpoint
• Wellpoint Cancer Care Quality Program employing NH technology to promote evidence based cancer pathways.
• Rationale:
• 1/3 of current treatments don’t follow best practice
• Cancer care costs to insurers are growing by 25% pa
• Doctors have information overload (180 journals per month!)
• Drugs are purchased directly by physicians and reimbursed on pass through plus
•
•
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Funding precision medicine in a UK setting ?
• National Tariff
• Central Funding – the 100,000 Genomes Project &
beyond
• The internal business case for personalised, proactive
& coordinated care
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The NantHealthValue Proposition in a UK context
Bosanquet & Evans Sept 2014
“Sustaining Universal Healthcare in the UK:
Making better use of information”
A detailed study of the potential for the deployment of (currently available ) healthcare informatics to drive efficiency in NHS
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The NantHealthValue Proposition in a UK context
1. A&E – improvements to diagnosis & care programmes of complex patients 10% of medical staff time (£5bn benefit)
2. Diabetes – If England used NHS Scotland informatics set1,775 fewer amputations (£37m benefit)
3. COPD – Finland TORCH Model showed benefit of home monitoring of patient compliance with therapies(mortality falls from 26% to 11%) means reduced admissions to hospital (£126m benefit)
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The NantHealthValue Proposition in a UK context
4. Chronic health readmission rates. Endorsed the findings
of a recent Liverpool University study showed big data solutions
would reduce trust 30 day readmission rates by 8-12% by condition
(benefit £17m pa)
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The NantHealthValue Proposition in a UK context
4. Cancer – improved data analytics focused on improved prescribing &
personalised medicine for cancer patients. This in turn will enable targeted and
reduced radiotherapy will lead to 30% less admissions (benefit £60m pa).
CONCLUSION – SIGNIFICANT POTENTIAL BENEFIT FROM ADOPTION OF
NANTHEALTH ADVANCED INFOMATICS IN UK CLINICAL PRACTICE
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The NantHealthValue Proposition in a UK context
• Colon Cancer £95m
• Rectal cancer £32m
• Lung cancer £111m
• Ovarian cancer £39mEstimate of the annual cost
impact of earlier diagnosis and
more targeted interventions of
main cancers in the UK
‘Saving Lives, Averting Costs Sept 2014’
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“Make doing the right thing the norm..”
“The C20th has given us a volume of knowledge and skill greater than any individual clinician can hold in their head or know how to deliver alone.
How do we solve that?
We need to make doing the right thing the norm…..through the use of computerised systems and checklists borrowed from the airline industry.
“The important thing is to make it easy anyone to follow”.
Dr Atul Gawande, 2014
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‣ Funding Availability:o Cost of sequencing decreasing rapidly;o Create markets for commercial clinical trials with a molecular target;o Commercialization of new novel diagnostics;o Opportunity for ‘private/co-pay’ for NGS;o NantHealth approach includes:o Waste reduction and effective care through: Deliver better cancer care integration and coordination; End to end cancer pathway design with explicit linkage to palliative care; Population health management; Applied informatics;
o Reprioritise IT focus to innovative and transformative IT: Deliver care integration via cOS innovations and ‘m-health’ Deliver TRUE population health;
o Accelerate clinical adoption and funding for personalised care: Target and support early adopter organisations; Accelerate ‘translation’ from discovery to routine use in practice; Inform and transform research; Work closely with other large scale programmes;
Challenges for Scaling NGS
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‣ Health System Governance:o Oversight and clinical engagement;
o Shared risk for new models of care;
‣ Technical Infrastructure;o Data centres with hyper secure ‘bio-encryption;’
o Dark fibre for secure high-speed data transfer;
o Supercomputing power for clinical interpretation and annotation;
o High-throughput sequencing and mass spectrometry;
o Extension of the patient record to support automation, standardisation and high-reliability;
‣ Academic Leadership & Education;o Convergence of clinical research and care delivery;
o Education and dissemination across clinical science, clinical and patient populations;
Challenges for Scaling NGS
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‣ Population Size;o Convergence of populations for molecular medicine;
o Participation in global learning networks to support learning and adoption;
‣ Regulatory;o Drug approvals requiring biomarker;
o Ethics and security models for molecular data management;
o Speed of laboratory accreditations for NGS capabilities;
‣ Leadership;o The will to make it happen.
o Win, win, win, win win – ‘what’s in it for me?’
Challenges for Scaling NGS
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Opportunity to deliver NGS as part of clinical practice is REAL, available now, and delivering;
‣ Better diagnosis and earlier intervention;
‣ Optimal treatment selection leading to higher quality and lower cost of delivery, particularly cost of second and third treatment lines;
‣ More efficient medicine development;
‣ Learning from other health systems currently deploying such approaches e.g. England, Scotland.
‣ Economic advantages to attract high-skilled workforce;
‣ Enhancing academic prowess of large teaching facilities and partner research groups, creating centres of innovation and excellence;
‣ Attracting significant additional research programmes;
‣ Maturing of health intelligence infrastructure to support new models of care, consistent with the principles of automation and high reliability.
In Summary: Opportunities for Scaling NGS
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www.nanthealth.co.uk
Martin Walsh
General Manager, NantHealth
Mobile: +447976 179563
martin.walsh@nanthealth.com
Paul Assinder
CFO, NantHealth
Mobile: +447973 398460
Paul.assinder@nanthealth.com
Tony Williams
Co-Director of ECMC
University of Southampton
apw2@soton.ac.uk