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Bridging Genomics and Therapy

– Creating a Theranostics

Paradigm

Samuel Abraham, PhDVP Strategic Relationships

BC Cancer Agency

Diponkar Banerjee MBChB, PhD, FRCPCExecutive Medical Director

PHSA Laboratories

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Provincial - Implementation of Cancer Control

DawsonCreekPrince Rupert

Terrace

Kitimat

PrinceGeorge

Kelowna

Vernon

Kamloops

Cranbrook

Nelson

Powell River

Creston

Vancouver

Trail

Fraser Valley (Surrey)

Chilliwack

Penticton

Vancouver Island(Victoria)

Nanaimo

Port Alberni

Comox

Campbell River

Whitehorse, Yukon

• Central Agency office

•Cancer Research Centre (Vanc. Vict)

•Regional Cancer Centres

•Community Cancer Centres

•Community Cancer Clinics

•70 regional pharmacies

•Networks:

•hereditary cancer

•cervical cytology

•colposcopy clinics

•screening mammography centres

•palliative care

•surgical oncology council & network

Cancer Centre and

Research Centre

Cancer Centre

Consultative Clinic

Screening

Mammography

Centres, Cervical

Cytology Screening

Program

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Theranostics

Theranostics is the term coined by PharmaNetics [Ltd] to describe the use of diagnostic testing to diagnose a given disease, choose the correct treatment regimen and dose, and monitor the patient response to therapy on an individualized basis.

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Utility of Theranostics

• Disease risk prediction

• Disease diagnosis

• Disease prognosis

• Patient stratification

• Therapeutic stratification

• Monitoring therapeutic response

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The Limitations of Today’s Drug Therapies –

selected examples

25%

30%

30%

47%

48%

50%

50%

57%

60%

60%

62%

70%

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Cancer (all)

Hypertension

Alzheimer's

Hepatitis C

Osteoporosis

Rheumatoid Arthritis

Migraine (Acute)

Diabetes

Asthma

Schizophrenia

Depression

Hypercholesterolemia

Dis

ease T

yp

e

Efficacy Rates

Average of all drugs = 60%)

From: Spear B et al. Trends in Molecular medicine Vol 7 201-204, 2001

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Drug Costs (Retail) in Canada

Estimated costs in 2006 = $25 billion

If, on average, 40% of drugs are ineffective, we are wasting $10 billion on useless therapy.

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IMPERATIVES

0

10000

20000

30000

40000

50000

1995

/96

1997

/98

1999

/00

2001

/02

2003

/04

2005

/06

2007

/08

2009

/10

2011

/12

Incidence Prevalence

• Incidence of Cancer

• Prevalence of Patients Receiving Drug Therapy

BC Cancer Agency Projections

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BC Cancer AgencyProjected Growth in Chemotherapy Drug Costs

($ Millions)

$0

$50

$100

$150

$200

$250

$300

95/9

6

96/9

7

97/9

8

98/9

999

/200

0

00/0

1

'01/

02

'02/

03

'03/

04

'04/

05

'05/

06

'06/

07

'07/

08

'08/

09

'09/

10

Non-drug global budget

Chemotherapy drug costs

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Emerging Paradigms Novel therapies will likely be gene-based

20% of current pharmaceutical R&D is gene-based – over 1600 gene based therapies are in development (66% in preclinical stage)*

Patient selection is required for targeted therapy (e.g. Herceptin) thus a predictive test for every new targeted therapy will be mandatory

Genetic analysis may predict for drug toxicity or efficacy (pharmacogenomics)

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Gene based R&D

51%

18%

12%8% 6% 5%

Cancer

Anti-Infective

Cardiovascular

Musculoskeletal

Neuro

Blood

Gene-based drug R&D programmes by therapy area

Source: R&Dfocus 2000

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Epithelial

progression

Survival

Predictive Diagnostic & Prognostic

Markers therapeutic Markers

Cancer

control

spectrumPrevention Early detection Diagnosis Treatment Palliation

End

points

Genomics

Cytology

Conventional Imaging

Histopathology

Surgery

Radiation

Systemic Therapy

DysplasiaCarcinoma

in Situ MetastasisHyperplasiaNormal

epitheliumLocally

Invasive Cancer

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Predictive and Personalized Oncology

Concept

All treated withchemotherapy

80% No therapy required

20% Therapy required

Unselected group Poor prognostic gene signature group

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Cost avoidance calculations for low grade

low stage breast cancer 2003

New

cases Node Neg Drug cost Radiation cost

Avoidable

costs @80%

BC 2,757 1,737 $7 million $5 million $10 million

Canada 21,200 13,356 $56 million $39 million $76 million

Developed

World 579,285 364,950 $1.5 billion $1 billion $2.1 billion

Global

1.05

million 661,500 $2.7 billion $2 billion $3.7 billion

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Cost avoidance calculations for low grade low

stage breast cancer - 2013

New cases Node

Negative

Drug cost Radiation

cost

Avoidable

costs @80%

BC 3,705 2,334 $100

million

$70

million

$136 million

Canada 27,505 17,328 $744

million

$517

million

$1 billion

Developed

World

751,579 473,495 $20 billion $14 billion $27 billion

Global 1.4

million

882,000 $38 billion $26 billion $51 billion

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When her hairdresser asked her last fall whether she would continue wearing her hair long, Elizabeth Sloan broke down crying.

Unbeknown to the hairstylist, Ms. Sloan had recently had a breast tumor removed and was expecting to begin chemotherapy, which would probably mean losing her hair.

But later that day, Ms. Sloan received the results of a new $3,500 genetic test, which indicated that her cancer probably would not come back even if she skipped chemotherapy.

"It was a huge relief," said Ms. Sloan, 40, a mother of two young boys who lives in Manhattan. "I did not want to napalm-bomb my body with chemicals."

The test taken by Ms. Sloan, known as Oncotype DX and offered by a company called Genomic Health, is part of a new wave of sophisticated genetic or protein tests that are starting to remake the diagnostics business, both for the technology they use and the way they are developed and sold.

April 13, 2006A Crystal Ball Submerged in a Test TubeBy ANDREW POLLACK

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Oncotype-DX

21 gene set (16 genes + 5 reference genes) – stratifies into low (score <18), intermediate (>18 < 30))and high (≥30) risk of recurrence at 10yrs

Works on formalin-fixed tissue

Recurrence score has predictive power beyond that of the St. Gallen or National Comprehensive Cancer Network risk stratification guidelines, sufficient to change some patient decisions about chemotherapy

About half of the 92% of patients who were in the high-risk National Comprehensive Cancer Network category were reclassified as low-risk by the recurrence score, with a 10-year relapse risk of 7% (CI, 4% to 11%)

From: Paik S. The Oncologist 2007; 12:631-635

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MammaPrint

70-gene signature Requires frozen tissue 40% of patients would fall into a good prognosis

group with 15% 10 yr recurrence rate (vs. 15% of patients being classified as within the good prognostic group by St. Gallen index)

33% of St. Gallen high risk group reclassified as low risk

From van de Vijver MJ et al. NEJM 2002 347: 199-2009

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Barriers to Theranostics The Pharmaceutical Industry’s blockbuster-drug business

model

The lack of interest in predictive tests from the drug industry – fear of loss of profits

Subset analysis of clinical trials results is discouraged

Funding mechanisms for drugs, physicians, and laboratories

Entrenched physician behaviour and unfamiliarity with concepts of genetic factors that influence response to drugs

Glacial pace of translating research discoveries to the clinical arena

Lack of funding from granting agencies for true translational research

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The Pharmaceutical Industry

Needs a Paradigm-Shift - 1

Threats

Drug companies spend ~$500 million in research for every drug that makes it to market (Includes the cost of drugs that fail).

Developing a predictive test could add an extra $100 million per drug.

For many targeted cancer drugs only a tenth of patients might be helped.

So investors backing the drug firm would spend 20% more to reach 90% fewer patients.

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Opportunities Rescue failed drugs

Reduce R&D costs

Faster FDA approval if trials are designed with biomarker-based stratification

Better results

Longer drug use to control disease

Reduce toxicity and side-effects

Partner with Health Authorities to reallocate resources from cost avoidance to introducing new targeted therapies.

The Pharmaceutical Industry

Needs a Paradigm-Shift - 2

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Challenges: Variations in the Human

genome

Type Frequency in human genome

Single nucleotide polymorphism (SNP)

12 million

Deletions/Insertions >1 million

Varying number of tandem repeats (VNTR)

>500,000

Copy number variations (CNV) >1500 loci (12% of genome)

Acquired Karyotypic and genetic abnormalities (mutations)

DNA methylation >20% of genome

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Post-transcription modifications that

influence gene product dose or function

MicroRNA (miRNA) – translational repression or mRNA degradation

Splice-variants

Post-translational modifications of proteins

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Quality Assurance Issues: Example Her2neu tests

in BC

Technologists and pathologists must be highly skilled

Need to test >100 cases a month to be proficient (JNCI 2002 94:788-789; 855-857)

Up to 33% of patients may be misclassified as Her2neu+ by small labs, with the following drawbacks:

Patients may inappropriately receive an expensive ($46,788) potentially cardiotoxic drug

No therapeutic benefit (the drug only works on a subset of true+ cases).

Decentralised testing may result in unnecessary drug expenditures of $12 million in an adjuvant setting

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Ethical Issues of Personalized

Therapy A technology that identifies patients who will

benefit from a given therapy automatically identifies those who won’t benefit – denial of therapy

“Never underestimate the desperation of a patient to obtain a drug” – Jan Platner (National Breast Coalition)

How accurate is the predictive test? –“Shopping” for a positive test

Offering toxic therapy to unselected patients (current practice)

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Thank you

Any questions?