Revolutionary Medicine: Opportunities and Challenges in .../media/Confederation...UK Cancer network...

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Revolutionary Medicine: Opportunities and Challenges in Delivering Molecular Diagnostics

NHS Confederation Annual Conference 2015

Confidential Copyright © Do not distribute – Last Updated 18-5-2015

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


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


Clinical decision-making is becoming more complicated


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


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


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)


Lung carcinomaEGFR KRAS BRAF mutation

ALK rearrangement by FISH

Ovarian carcinomaTP53 PTEN PIK3CA BRAF mutation


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)


Genomics & Proteomics


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.


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

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

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

http://www.southampton.ac.uk/youreit

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


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


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


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


The NantHealthValue Proposition – the response 1

• Government Employees Hospital Association (GEHA)

•

•

•


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

•

•


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


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



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)



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)



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



• 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’


“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


‣ 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


‣ 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;



‣ 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?’



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


www.nanthealth.co.uk

Martin Walsh

General Manager, NantHealth

Mobile: +447976 179563

[email protected]

Paul Assinder

CFO, NantHealth

Mobile: +447973 398460

[email protected]

Tony Williams

Co-Director of ECMC

University of Southampton

[email protected]

http://www.nanthealth.co.uk

http://www.nanthealth.co.uk/

Revolutionary Medicine: Opportunities and Challenges in .../media/Confederation...UK Cancer network...

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