1. Stratified Medicine – Implications for
pharmaceutical development
BioDundee 2012

2. from Janet Woodcock, Director of CDER, FDA
“...the upcoming years may well be known as the age of diagnostics”
April 2012

3. Personalized Medicine Saves Lives
100
5 Year
Years Ago
Survival
80
Years Ago “Disease of the Blood”
~ 0%
60 Leukemia or Lymphoma
Years Ago
Chronic Leukemia Indolent Lymphoma
Acute Leukemia Aggressive Lymphoma
Preleukemia
38 Leukemia types identified: 51 Lymphomas identified:
Acute myeloid leukemia (12 types) Mature B-cell lymphomas (14 types)
Today Acute lymphoblastic leukemia (2 types) Mature T-cell lymphomas (15 types)
Acute promyelocytic leukemia (2 types) Plasma cell neoplasm (3 types)
Acute monocytic leukemia (2 types) Immature (precursor) lymphomas (2 types)
Acute erythroid leukemia (2 types) Hodgkin’s lymphoma (5 types)
Acute megakaryoblastic leukemia Immunodeficiency associated lymphomas (5 types)
Acute myelomonocytic leukemia (2 types) Other hematolymphoid neoplasms (7 types)
Chronic myeloid leukemia
Chronic myeloproliferative disorders (5 types)
Myelodysplastic syndromes (6 types)
Mixed myeloproliferative/myelodysplastic syndromes (3 types) 70%
Ries LAG, Eisner MP, Kosary CL, Hankey BF, Miller BA, Clegg L, Mariotto A, Feuer EJ, Edwards BK (eds). SEER Cancer Statistics Review, 1975-2002, National Cancer
Institute. Bethesda,MD, http://seer.cancer.gov/csr/1975_2002/, based on Nov 2004 SEER data submission, posted to
the SEER web site 2005.

4. Stratified Medicine and Theranostics are a
New Concept
©Lab21 May 2012

5. Primary resistance and impact on first HIV therapy
Patient 97-513
(blue):
Wild-type
sensitivity
Patient 98-1186
(red):
Mutations present
for AZT, 3TC and
multiple PI
resistance Little SJ et al. JAMA 1999; 282: 1142-1148.

6. Protease Gene Mutations Selected by PIs
L K L V M M I A G V V I L
IDV 10 20 24 32 36 46 54 71 73 77 82 84 90
IRV MR I I I IL V VT SA I AFTS V M
L
RTV 10 20 32 33 36 46 54 71 77 82 84 90
FIRV F VL
G
SQV 10 48 54 71 73 77 82 84 90
IRV V S A
D N
NFV 10 30 36 46 54 71 77 82 84 88 90
FI N DS
I I
APV 10 32 46 47 50 54 73 84 90
FIRV V V LVM
F L
LPV/r 10 20 24 32 33 46 47 50 53 54 63 71 73 82 84 90
L VL P AFTS
Multi-PI 10 46 54 82 84 90
Resistance
VML
Primary Undetermined Significance
©Lab21 May 2012 Secondary

7. Increasing Prevalence of Resistance Mutations
• Researchers reported after studying nearly 12,000 HIV patients in the US
during 1999
• More than one fourth of patients have viral resistance to 3 major
classes of HIV drugs
• 29% of patients have virus that is resistant to 2 classes of drugs
• 22% of patients have virus that is resistant to a single class of drugs
• Indicates that:
• Careful monitoring needs to be implemented during therapy
• Preliminary characterisation of all individual HIV patients must be
implemented BEFORE therapy is initiated
• This has to be factored when designing all new antiretroviral clinical
trials
Bloor. Antivir Ther 2000;5(suppl 3):132.
©Lab21 May 2012

8. TRUGENE HIV-1 Genotyping Test—the First FDA
Cleared HIV Resistance Test
• Market clearance for TRUGENE HIV-1 Genotyping Kit and OpenGene DNA
Sequencing System received September 26, 2001
• First HIV drug resistance test to receive market clearance from the FDA
• First IVD pharmacogenomics test to receive FDA clearance
• Integrated system comprised of the chemistry, hardware, software,
interpretative patient report, training, certification and service

10. EGFR Pathways and Drug Targeting

11. Iressa analysis in NSCLC by EGFR status
©Lab21 May 2012

12. Analysis of CRC response to EGFR inhibitors
©Lab21 May 2012

13. EGFR Pathways and Drug Targeting

14. Erbitux and Vectibix only effective in 10-20% of resistant
metastatic colorectal cancer
38%
Kras mut
Kras Mutants
Kras wt/Braf
52% Mutants
?
Kras wt/?
14%
Braf
mut
©Lab21 May 2012

15. Vemurafenib
PFS – 5.3 months vs 1.6 months
Chapman et al, NEJM, 2011
On August 17, 2011, the Food and Drug Administration (FDA) approved
vemurafenib (Zelboraf, Hoffmann-La Roche Inc.) for the treatment of patients
with unresectable or metastatic melanoma with the BRAFV600E mutation

16. Rapid Response of Metastatic Melanoma
using Vemurafenib
©Lab21 May 2012

17. R&D Productivity is on the decline
NMEs per $B R&D spent (inflation adjusted)
100
10
1
0.1
1950 1980 2010
Source: Bernstein Research ―The Long View – R&D Productivity 2010)

18. Drug Discovery Pipeline Improvement
― 79 per cent of candidate drugs that currently fail in clinical development
might actually succeed if they were tested only on sub-populations known
to be most susceptible to their beneficial effects and least susceptible to
side effects‖

19. Parallel Track Dx and Rx Development
Pharmaceutical
Preclinical Phase 1 Phase II Phase III Launch
Launch
Discovery Validation Development Implementation Regulatory
Robustness Clinical Validation
Reproducibility
Dx Marker

20. FDA Approval for Vemurafenib
On August 17, 2011, the Food and Drug Administration (FDA) approved
vemurafenib tablets for the treatment of patients with unresectable or
metastatic melanoma with the BRAFV600E mutation as detected by an FDA-
approved test.
The approval was based on an international randomized open-label trial in
patients with previously untreated metastatic melanoma with the BRAFV600E
mutation as detected by the Cobas 4800 BRAF V600 Mutation Test (made by
Roche Molecular Systems, Inc.). This companion diagnostic test was
approved by the FDA concurrently with vemurafenib’s approval.
FDA approves Xalkori with companion diagnostic for a type of late-
stage lung cancer
Second targeted therapy approved with a test this year
On August 26, 2011 the U.S. Food and Drug Administration approved Xalkori
(crizotinib) to treat certain patients with late-stage (locally advanced or
metastatic), non-small cell lung cancers (NSCLC) who express the abnormal
anaplastic lymphoma kinase (ALK) gene.
Xalkori is being approved with a companion diagnostic test that will help
determine if a patient has the abnormal ALK gene, a first-of-a-kind genetic
test called the Vysis ALK Break Apart FISH Probe Kit. It is the second such
targeted therapy approved by the FDA this year.
©Lab21 May 2012

21. The Emergence of Next-Generation Sequencing
Pharmaceutical industry
Diagnostic industry
Current levels of drug performance are far from
satisfactory
“Today, the response rates
vary from 20% to
75%, depending on the drug
and the disease”
Jürgen Schwiezer
CEO, Roche
Health Regulators
Drug approval agencies are encouraging
greater use of biomarkers and diagnostics in
drug development and prescribing decisions,
thus promoting the concept of companion
diagnostics for drugs
Source: PricewaterhouseCoopers “Moving towards personalized
healthcare”

22. Parallel Track Dx and Rx Development
Pharmaceutical
Preclinical Phase 1 Phase II Phase III Launch
Launch
Discovery Validation Development Implementation Regulatory
Robustness Clinical Validation
Reproducibility
Dx Marker

23. Trofile Model
• Pfizer developed a new HIV-1 inhibitor – Maraviroc/Celsentri
• Maraviroc only functions against CCR5-tropic viruses and has no effect on CXCR4 so clear
need to differentiate between the virus in an individual patient
• Pfizer commissioned Monogram Biosciences (San Francisco) to develop a test (Trofile) that
would differentiate the two strains
• Assay used intensively during the trials and was fully operational when drug was launched
• Assay only run in California so local operators were appointed in specific regions to
facilitate sample logistics
©Lab21 May 2012

24. What are LDTs ?
• Assays or “kits” developed and “validated” by a laboratory/institution
• Currently regulated by CLIA, HCFA and/or state (if in the U.S.) but not
the FDA
• No official requirements for design control, clinical trials,
QSR(GMP)manufacture and quality control nor review and approval by a
recognized regulatory body of a 510(k) submission and product “labeling”
• No requirement for clinical validation
• Pricing is typically low ( $200-450)

25. Laboratory Developed Tests:
Pre-marketing requirements
• For a test system developed in-house or, where the performance
specifications are not provided by the manufacturer, the lab has to
establish:
• Accuracy
• Precision
• Analytical sensitivity
• Analytical specificity
• Reportable range of the test system
• Reference intervals (normal values)
• Other performance criteria required

26. US: Unequal Regulation of IVDs
IVD Manufacturer CLIA Certified
Lab
IVD Kit Laboratory Developed
Test (LDT)
FDA
FDA Enforcement Discretion

27. Vertically Integrated Diagnostics
• Independent and platform agnostic
• Can develop assays for appropriate biomarker
• Has accredited laboratories in key global locations
• Fully optimise and validate assay
• Run clinical trials (GCLP)
• Run assays as LDTs (CLIA, CPA, CAP)
• Support clinical validation
• Full regulatory and manufacturing capability (GMP)
• CE mark (ISO)
• 510(K)
• PMA
• Global sales and marketing/distributor network to cover all geographies
©Lab21 May 2012

28. Conclusion
• Pharma/Dx partnership is extremely important to maximise efficiency of
stratified medicine
• It is critical that all parties adopt a far more stringent approach to
protection of IP, regulatory compliance and quality control
• Many lessons to be learnt from therapeutic areas where personalised
medicine has been in place for many years
• Diagnostic companies may not differentiate a companion diagnostic from
any other of their diagnostic tests within their business model
• All parties: healthcare providers, government agencies, pharma,
diagnostic companies and, most important, patients should be able to
maximise value from stratified medicine
©Lab21 May 2012