2/27/15

The History & Impact of Diagnostics

Personalized Medicine
and
Companion Diagnostics

Mara  G.  Aspinall,  ASU  Professor  of  Prac:ce    

mara.aspinall@asu.edu  
Course  Faculty,  Co-­‐Founder,  School  of  Biomedical  
Diagnos:cs    
 

The Myth:
Medicine is an objective and definitive science

The Reality:
Medicine is
a science of uncertainty &
an art of probability.

Dr. William Osler (1849–1919)

Diagnosis is not the end, but the beginning of practice.

Martin Fischer

For most diagnoses all that is needed is an ounce of knowledge,

an ounce of intelligence, and a pound of thoroughness.
Arabic Proverb

A Patient has nothing without an Accurate and Timely Diagnosis.

Mara G. Aspinall

1  
 2/27/15  

Diagnostics has made Great Strides

Google Contact Lens

Glucose Meter

Blood Glucose
Meter
Urine Test Strip

Constantine tastes
patients' urine

4  
Copyright 2015 Aspinall. Do not Distribute or Reproduce

History  of  Medicine  

Folklore & Scientific Clinical Personalized
Superstition Exploration Trial & Error Medicine

BC 0 - 1700 AD 1700 - 1965 1965–

 

l  Diseases were sent as a punishment from the gods

Copyright 2009-2015 Aspinall. Do not Distribute or Reproduce

History  of  Medicine  

Folklore & Scientific Clinical Personalized
Superstition Exploration Trial & Error Medicine

BC 0 - 1700 AD 1700 - 1965 1965–

 

•  182 – Galen connects paralysis with spinal cord severance

•  1492 – da Vinci combines human dissections with anatomical drawing
•  1543 – Vesalius publishes The Fabric of the Human Body
•  1578 – Closed loop blood circulatory system defined by Harvey
•  1590 – Janssen invents the microscope

Copyright 2009-2015 Aspinall. Do not Distribute or Reproduce

2  
 2/27/15  

History  of  Medicine  

Folklore & Scientific Clinical Personalized
Superstition Exploration Trial & Error Medicine

  BC 0 - 1700 AD 1700 - 1965 1965–

 
•  1747 – First Clinical Trial: James Lind discovers citrus prevents scurvy
 
•  1816 – Rene Laennec invents the stethoscope
•  1866 – Mendel discovers genes (in peas)
•  1870 – Pasteur and Koch establish the germ theory of disease
•  1904 – Medical Schools standards established, college required
•  1922 – Insulin first used to treat diabetes
•  1925 – Vaccination use begins (whooping cough, TB, tetanus, etc.)
•  1945 – Pharmaceutical Industry established, use of antibiotics begins
•  1953 – DNA’s structure discovered
•  1962 – Clinical Trials required by law for FDA Drug Approval
Copyright 2009 - 2015 Aspinall. Do not Distribute or Reproduce

History  of  Medicine  

Folklore & Scientific Clinical Personalized
Superstition Exploration Trial & Error Medicine

BC 0 - 1700 AD 1700 - 1965 1965 –

•  1965 – First Ultrasound

•  1968 – First ImmunoAssay 1972 – Radio IA 1978 – Enzyme IA
•  1971 – First CAT scanner (later called CT)
•  1971 – First Magnetic Resonance Imaging (MRI)
•  1972 – DNA / Molecular Cloning invented
•  1976 – First Commercial PET Scanner
•  1976 – Biotechnology industry established
•  1985 – PCR invented by Kary Mullis
•  1989 – DNA Microarray invented by Stephen Fodor
•  2003 – First Human Genome Sequence completed

Copyright 2009- 2015 Aspinall. Do not Distribute or Reproduce

Modern Diagnostics is very recent history

Individual  Physicians   Laboratory  Science  
Knowledge:  
Medicinal  Herbs  
Galen  (dissec:on)   Vesalius  1543  
129-­‐216   Physiology  &  Anatomy   (Human  Anatomy)  
Pasteur  &  Koch   Prusiner  
(Germ  Theory)1870   Role  of  Pathogens   (Prions)  1982  
Tools:   Human  Genome  
Project  “complete”  2003  Systems  biology    
Physicians  5  senses  
Fahrenheit   Laennec  
(Thermometer)  1714   Simple  devices   1816  (Stethoscope)  
Pravaz  &  Wood   Damadian  
(Blood  test  Syringe)  1853   Engineered  machines   1971  (MRI)  
Abbo^  (EIA)  
Health  Impact:   1978   Automated  Systems  
Surgery  &  natural  herbs  
Prognosis  
Snow   Doll  
(Typhoid)1854   Public  Health   1954  (Lung  cancer)  
Behring   Fleming  
Disease  focused  Tx  
(Serum  Tx  )1891   1943  (Penicillin)  
Druker  
(Gleevec  )1998   Individual  Tx  

Copyright 2015 Aspinall. Do not Distribute or Reproduce

3  
 2/27/15  

History and Future of Diagnostics

Diagnostics 5.0 = Prevent Disease?

Multiple Technologies

Diagnostics 4.0 = Identify Risk?

Genomics

Diagnostics 3.0 = What Sub-Type?

Automated Instruments & Algorithms

Diagnostics 2.0 = What Disease?

Semi-Automated Instruments

Diagnostics 1.0 = Is There Disease?

MD’s 5 Senses
10

Knowledge drives Diagnosis

Knowledge of Tools to enhance
disease pathology powers of observation

Diagnosis  
(from  Greek  diagnos:cs  –  “able  to  dis:nguish”)  
Iden:fying  an  illness  by  examina:on  of  signs  &  symptoms  

Prognosis Action
How will the illness progress? What can be done to help?
•  Odds of recovery, contagion, etc. •  Patient therapy
•  Evolution of disease •  Public Health (Quarantine, etc.)

Copyright 2015 Aspinall. Do not Distribute or Reproduce

Therapy creation drives Diagnosis

Detailed  diagnosis  
essen:al  for  effec:ve  
Many   therapy  

More  
treatment  
Op:ons  

None  

Prognosis   Comprehensive  
only   diagnosis  
12  

Copyright 2013-2015 Aspinall. Do not Distribute or Reproduce

4  
 2/27/15  

Diagnostics Bridge Theory to Therapy

Solid   Targeted  Treatments  –  Radia:on       Treatable  
Tumors  
Biomarker  Driven  Companion  DiagnosAcs  

An:viral  Therapies  
AIDS   Treatable  

Dx:  Viral  Load  &  Genotyping  

Chemotherapy   Treatable  
Liquid  
Tumors  
Dx:  Disease  Characteriza:on  

Blood   Treatable  
Strokes   Thinners    
Dx:  Coagula:on  Tes:ng  

An:bio:cs  
Infec:ous   Treatable  
Disease  
Dx:  Microbial  Tes:ng  

Diabetes   Insulin   Treatable  

         Dx:  Urine  Strips  

1920   1950   1960   1970   1980   1990   2000   Today  

13  
Copyright 2011- 2015 Aspinall. Do not Distribute or Reproduce

Diagnostics are Not Just for Diagnosis Anymore

Diagnostics 5.0

Treatment  
Screening   Diagnosis   Sub-­‐Typing   Prognosis   Monitoring  
SelecAon  

Am I at Am I sick? Which sub- How long Which Is treatment

risk? type? do I have? treatment working?
What
at what
disease?
dose?

The So What? Test

14  
Copyright in parts 2014- 2015 Aspinall. Do not Distribute or Reproduce

From 161 Diseases to >16,000 in 120 Years

Source: History of the Statistical Classification of Diseases and Causes of Death, I. Moroyama, et. Al, 2011; International Classification of Diseases, Tenth Revision, (ICD-10)

15

5  
 2/27/15  

Trial & Error: The Old Paradigm

                                                                                                                                                                     
AcAon   Successful  When  it  Leads  to  
InnovaAon  and  Improves  
Standard  of  Care.  

Fails  When  We  SeNle  for  

“Trial  and  Error”  Medicine  AS  
the  Standard  of  Care.  

Copyright 2011-15 Mara G. Aspinall Do not Distribute or Reproduce

Personalized Medicine: New Paradigm  

 

Linking  Tests  to  Ac/on  and  Therapy    

ObservaAon   Test   AcAon   Predicted  

Response  

Breaking  The  Cycle  of  Trial  and  Error  

Copyright 2011-2015 Mara G. Aspinall Do not Distribute or Reproduce

Personalized Medicine Test Categories  

Drug Selection
Breast Cancer Herceptin® HER2
Drug Dosage
Acute Lymphoblastic Leukemia mercaptopurine, thioguanine, TPMT
azathioprine

Drug Efficacy / Resistance

Chronic Myelogenous Leukemia Gleevec® Quant BCR-ABL

Monitoring / Disease Status

Chronic Lymphocytic Leukemia Campath® Minimal Residual Disease

Recurrence Risk
Breast Cancer Chemotherapy OncoType DX®

Predisposition
Breast and Ovarian Cancer BRACAnalysis®

Copyright 2009-2015 Mara G. Aspinall Do not Distribute or Reproduce

6  
 2/27/15  

KRAS Testing in Colon Cancer

Alterna:ve  Treatment  
KRASTes:ng  
!  
!  
!  !  
!  
!   !  
!  
!  !  
!  
!  
!   !  
!  
!  !  
!   Treat  with  Erbitux  

!  
!  
!  !  
!  
!  
!   !   50%  

!  
!   Treat  with  Erbitux  
Treatment  

!  
!   !  
!  
!  !  
!   Success  

!  
!  
!  !  
!   30%   !  
!  
!  
Langreth,  R.  (2008),  ‘Imclone’s  Gene  Test  Ba^le’,  Forbes.com,    
16May    Lièvre  et  al.  J  Clin  Oncol.2008;  26:  374-­‐379  

For All The Promise of Biomarkers……

Thousands    
of  claimed  
biomarkers  
documented  in  
100    
150,000   biomarkers  rouAnely  
publicaAons     used  in  the  clinic    

Adapted  from  Nature  (2011);  469:  156–157   20  

Adoption of a New Biomarker

NY Times
“Next Nobel Prize”
J. Lab. Med. Editorial
“Important in a small %
Positive
Buffalo Evening News of patients”
Effect
NEJM
“Needs repeating”
Ultimate Estimate of RR

Ca Res
(or Predictive Value)

Benefit

Neutral

(RR=1)
J Clin Onc

J Immuno

Histo

NEJM
Negative
“15 years after discovery,
Ann. Int. Med editorial Big Pharma announces
Effect

“Doesn’t work & we knew a breakthrough. While testing
it wouldn’t 5 years ago” has been available for 10 years
it took until now to design and
obtain approval for a treatment.”

Adapted from D. Hayes, in Prin. Molec. Oncol., Humana Press, 2000

7  
 2/27/15  

Biomarkers Increase Drug Development Success

787  
Oncology 687  
NME’s
No  Biomarker  
1999-2008

The
121   114  
With  Biomarker   Biomarker
908  Industry  NMEs   801  NMEs  
into  Phase  1   Transi:oned  from  
Advantage
Phase  1  

No  Biomarkers   With  Biomarkers              

23%  P(success)   53%  P(success)  

90.4%   85.0%  
76.4%   69.0%  
50.8%   58.5%  

Phase  I   Phase  II   Phase  III   Phase  I   Phase  II   Phase  III  
22  
Source:  Hayashi,  K.  et  al;  Impact  of  biomarker  usage  on  oncology  drug  development,  February,  2013;  Journal  of  Clinical  Pharmacy  and  Therapeu:cs    

Blood Cancer at Diagnostics 4.0

5 Year
∼38 types of leukemia: ∼51 types of lymphoma: Survival
Acute myeloid leukemia (>12 types) Mature B-cell lymphomas (∼14 types)
Acute lymphoblastic leukemia (2 types) •  Mantle cell lymphoma (t11;14)
Today Acute promyelocytic leukemia (t 15;17) •  Follicular lymphoma (t14;18) 70%
Acute monocytic leukemia (2 types) •  Burkitt lymphoma (t8;14)
Acute erythroid leukemia (2 types) Mature T-cell lymphomas (15 types)
Acute megakaryoblastic leukemia Plasma cell neoplasm (3 types)
Acute myelomonocytic leukemia (2 types) Immature (precursor) lymphomas (2 types)
Chronic myeloid leukemia (bcr-abl+) Hodgkin lymphoma (5 types)
Chronic myeloproliferative disorders (5 Immunodeficiency associated lymphomas
types) (∼5 types)
Myelodysplastic syndromes (6 types) Other hematolymphoid neoplasms (∼7
60 Mixed myeloproliferative/myelodysplastic types)
Years ago syndromes (3 types)

Chronic leukemia Indolent lymphoma

80 Acute leukemia Aggressive lymphoma
Years ago Pre-leukemia
100
Years ago Leukemia or lymphoma

“Disease of the blood” ~0%

23  
Ries LAG, Eisner MP, Kosary CL, Hankey BF, Miller BA, Clegg L, Mariotto A, Feuer EJ, Edwards BK (eds).
Copyright 2012 Aspinall. Do not distribute or reproduce. SEER Cancer Statistics Review, 1975-2002, NCI http://seer.cancer.gov/csr/1975_2002

Colorectal Cancer at Diagnostics 3.5

Adenocarcinoma Mixed adenoneuroendocrine carcinoma
•  Papillary adenocarcinoma 5 Year
EC cell, serotonin producing NET
•  Tubular adenocarcinoma Gastrin producing NET (gastrinoma) Survival
•  Mucinous adenocarcinoma
•  Poorly cohesive carcinoma Mesenchymal tumours
•  Mixed adenocarcinoma
Adenosquamous carcinoma
•  Glomus tumor 90%
Today •  Granular cell tumor
Carcinoma with lymphoid stroma •  Leionyoma
Hepatoid adenocarcinoma •  Plexiform fibromyxoma
Squamous cell carcinoma •  Schwannoma
Undifferentiated carcinoma •  Inflamatory myofibroblastic tumor
•  Gastrointestinal stromal tumor
Neuroendocrine tumor (NET) •  Kaposi sarcoma
•  NET G1 (carcinoid) •  Leiomyosarcoma
•  NET G2 •  Synovial sarcoma
Neuroendocrine carcinoma (NEC) • MMR status
•  Large cell NEC •  Lynch/HNPCC
•  Small cell NEC • KRAS status
• BRAF status
30
Years ago TNM staging
Lynch / HNPCC
Sporadic cancers
100
Years ago
Identification of the hereditary link between certain colorectal cancers and
6,000 inheritance as a risk factor – now known as Lynch Syndrome
Years ago ~0%
“Gastrointestinal illness” treated with herbs by ancient civilizations
24  
Copyright 2012 Aspinall. Do not distribute or reproduce.

8  
 2/27/15  

 
  Pancreatic Cancer Still at Diagnostics 2.5
5 Year
Survival

PancreaAc  Adenocarcinoma  (80%+)     5%

Today   CysAc  neuroendocrine  
Epithelial  cysAc  tumors    
Acinar  cell  carcinoma  (exocrine)  
Solid  pseudopapillary  tumor  
Giant-­‐cell  tumor  
PancreaAco-­‐blastoma  
30    
Years  ago  
80     Resectable cyst Non-resectable cyst
Years  ago   (malignancy unknown) (malignancy unknown)
100    
Years  ago   Pancreatic cancer

“Internal organ disease – inflammatory or proliferative (1824)”

~0%

Garcia et al. Cystic Lesions of Pancreas-Pancreatology 2008;8:236–251; Cardenes, Higinia et.al.

Pancreatic Ca: Current Therapeutic Approach: The Oncologist 2006; 11:612-623.
25  

The Need for Change

Source: Aspinall and Hamermesh, Harvard Business School, October 2007 Do not Distribute or Reproduce

New Rx are too expensive for Trial & Error

Paroxysmal Hunter Maroteaux- Hereditary Infantile

Nocturnal Syndrome Lamy Angioedema Spasms
Hemoglobinuria $375,000 pa Syndrome Syndrome $300,000
$409,500 pa $365,000 pa $350,000 pa (One-time)

Pompe Anti Gaucher Fabry Hurler

Disease Inflamatory Disease Disease Syndorme
$300,000 pa $250,000 pa $200,000 pa $200,000 pa $200,000 pa
27
Copyright 2015 Aspinall. Do not Distribute or Reproduce; Data Source: www.cancer.org

9  
 2/27/15  

Clinical Trial Impact on HER2/Herceptin

Trial Design With HER2 neu Without

# of Patients 470 2,200
Response Rate 50 % 10 %
Years of Follow-up 1.6 10

•   Savings  in  clinical  trial  costs  ~  $  35  million  

•   Income  from  8  year  accelera:on  of  product  ~  $  2.5  billion  
•   Access  to  drug  from  accelera:on  ~  120,000  pa:ents  
From  Press  and  Seelig,  Targeted  Medicine  2004,  New  York,  November  2004  

The Gefitinib (Iressa®) Challenge  

EGFR mutation positive EGFR mutation negative
GefiAnib  (n=132)   GefiAnib  (n=91)  
CarboplaAn  /  paclitaxel  (n=129)   CarboplaAn  /  paclitaxel  (n=85)  
1.0   1.0  
Probability of progression-free survival
Probability of progression-free survival

HR  (95%  CI)  =  0.48  (0.36,   HR  (95%  CI)  =  2.85  (2.05,  3.98)  

0.8
0.64)     0.8
 p<0.0001  
p<0.0001   No.  events  gefi/nib  ,  88  
No.  events  gefi/nib,    97   (96.7%)  
0.6 (73.5%)   0.6 No.  events  C  /  P,  70  (82.4%)  
No.  events  C  /  P,    111  
(86.0%)  
 
0.4 0.4

0.2 0.2

0.0
0.0
0 4 8 12 16 20 24 0 4 8 12 16 20 24
At risk : Months Months

Gefitinib 132 108 71 31 11 3 0 91 21 4 2 1 0 0

C / P 129 103 37 7 2 1 0 85 58 14 1 0 0 0

ITT population
Cox analysis with covariates Treatment by subgroup interaction test, p<0.0001

Paradigm Shift

Historical     Today  &  Future    

We  have  the   I  have  A  
Drug   PaAent    
   
         
   
   
   
Find  me   Find  me  the  
PaAents   Drugs    
Copyright  2011-­‐15    Aspinall.  Do  not  Distribute  or  Reproduce  

10  
 2/27/15  

Pharma Opportunity: Companion Therapeutics

 
 

 Diagnos:c  Impact,  25  %  Marker  Frequency  

Without With Diagnostic
Measure Diagnostic Scenario 1 Scenario 2 Scenario 3
Market Size (patients) 200,000 50,000 50,000 50,000

Response Rate 25% 50% 75% 90%

Peak Market Share 20% 80% 80% 95%

Patients Treated 40,000 40,000 40,000 47,500

Resonders 10,000 20,000 30,000 42,750
Non-responders 30,000 20,000 10,000 4,750

Total Cycles (6 per responder 120,000 160,000 200,000 266,000

2 per non-responder)

Price Per Cycle $1,000 $1,000 $1,000 $1,000

Peak Sales $ 120 million $ 160 million $ 200 million $ 266 million

John  C.  Lechleiter,  PhD,    Eli  Lilly  and  Company   +  33  %   +  66%   +  122  %  

Cancer  Treatment  Today  

ORGAN-­‐Based  Treatments  
Pancrea:c  
Leukemia   Cancer  

Brain  
Cancer  
Lung  
Cancer  

Colon   Breast  
Cancer   Cancer   32  
Copyright  Mara  G.  Aspinall  2009-­‐2013  Do  not  copy  or  distribute.      

Cancer  Treatment  In  The  Future  

Biomarker-­‐Based  Treatments
c-­‐kit  
Jak-­‐2  

PDL-­‐1  
EGFR  

K-­‐ras  
Her-­‐2   33  
Copyright  Mara  G.  Aspinall  2009-­‐2013  Do  not  copy  or  distribute.      

11  
 2/27/15  

History and Future of Diagnostics

Diagnostics 5.0 = Prevent Disease?

Multiple Technologies

Diagnostics 4.0 = Identify Risk?

Genomics

Diagnostics 3.0 = What Sub-Type?

Automated Instruments & Algorithms

Diagnostics 2.0 = What Disease?

Semi-Automated Instruments

Diagnostics 1.0 = Is There Disease?

MD’s 5 Senses
34

Diagnos:cs  5.0  is  Technology  Agnos:c    

Clinical   IHC   Immuno-­‐   FISH   PCR   Imaging    

Chemistry   Assay  

!   !   !   !   !   !  

Liquid   Next   ComputaAonal  

Biopsy     GeneraAon   Pathology    
Sequencing  
35

Why Now?
Diagnostic Technology Has Improved

Past – Macro Level Testing

Tests differentiated disease from non-disease
Disease defined by location and size

Today – Molecular Level Testing

Disease defined by individual biology and /or
DNA of tumor or virus
Tests to subcategorize disease:
predict outcomes of specific therapeutic
screen for adverse events
monitor disease

12  
 2/27/15  

Why Now?
Diagnostic Technology Has Improved
 

Precision Testing
Multiple technology platforms
Multi-factorial testing
Multi-gene signatures
Multiple Sample Types –
Urine, Saliva, Breath, Hair, others?
Increased Use of Diagnostic Imaging
&
Availability of these Tests by Consumers
   
 

Diagnos:cs:  60%  decisions  –  2%  of  costs  

What disease? What stage? Patient’s CBC? What

is the patient’s blood pressure? Blood sugar?
Creatinine level? Is the tumor hormone positive?
What’s the right drug? Should the patient be given
hormone therapy? What other drugs could be used?
What’s the prognosis?

2% 60%
Healthcare spending Medical decision-making
accounted for by IVD influenced by IVD
Sources: European Diagnostic Manufacturers Association (EDMA), 2009; Lewin, The Value of Diagnostics - Innovation, Adoption and Diffusion into Health Care, 2005
38  

Diagnosis Save Lives

Diagnosis Save Money

Copyright  2011  Aspinall.  Do  not  Distribute  

or  Reproduce  

13  
 2/27/15  

Explosion of the “Omics”

q  Proteomics   o  Cytomics  
q  Allergenomics  
q  Bibliomics   o  Degradomics  
q  Biomics   o  Ecotoxicogenomics  
q  Cardiogenomics   o  Eicosanomics  
q  Cellomics  
q  Chemogenomics   o  Embryogenomics  
q  Chemoproteomics   o  Enviromics  
q  Chroma:nomics   o  Epigenomics  
q  Chromonomics   o  Epitomics  
q  Chromosomics  
q  Combinatorial  Pep:domics   o  Expressomics  
q  Computa:onal  RNomics   o  Fluxomics  
q  Cryobionomics   o  Fragmentomics  
q  Crystallomics  
q  Cytochromics   o  Fragonomics  
o  Etc…  
 

h^p://www.genomicglossaries.com  
Copyright  2011  Aspinall.  Do  not  Distribute  
or  Reproduce  

14