Stratified Medicine – Implications for

pharmaceutical development

BioDundee 2012

from Janet Woodcock, Director of CDER, FDA

“...the upcoming years may well be known as the age of diagnostics”

April 2012

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.

Personalized Medicine Saves Lives

80

Years Ago

Leukemia or Lymphoma60

Years Ago

Chronic Leukemia

Acute Leukemia

Preleukemia

Indolent Lymphoma

Aggressive Lymphoma

100

Years Ago

“Disease of the Blood”

Today

38 Leukemia types identified:

Acute myeloid leukemia (12 types)

Acute lymphoblastic leukemia (2 types)

Acute promyelocytic leukemia (2 types)

Acute monocytic leukemia (2 types)

Acute erythroid leukemia (2 types)

Acute megakaryoblastic leukemia

Acute myelomonocytic leukemia (2 types)

Chronic myeloid leukemia

Chronic myeloproliferative disorders (5 types)

Myelodysplastic syndromes (6 types)

Mixed myeloproliferative/myelodysplastic syndromes (3 types)

51 Lymphomas identified:

Mature B-cell lymphomas (14 types)

Mature T-cell lymphomas (15 types)

Plasma cell neoplasm (3 types)

Immature (precursor) lymphomas (2 types)

Hodgkin’s lymphoma (5 types)

Immunodeficiency associated lymphomas (5 types)

Other hematolymphoid neoplasms (7 types)

5 Year

Survival

~ 0%

70%

Stratified Medicine and Theranostics are a

New Concept

©Lab21 May 2012

Patient 97-513

(blue):

Wild-type

sensitivity

Patient 98-1186

(red):

Mutations present

for AZT, 3TC and

multiple PI

resistance

Primary resistance and impact on first HIV therapy

Little SJ et al. JAMA 1999; 282: 1142-1148.

©Lab21 May 2012

Protease Gene Mutations Selected by PIs

SQVIRV

10

G

V

48 54 71

S

73 77

A

82 84 90

NFVFI

10

D

N

30 36 46 54 71 77 82 84

N

DS

88 90

Multi-PI

Resistance10 46

VML

54 82 84 90

IDV

L

IRV

10

K

MR

20

L

I

24

V

I

32

M

I

36

M

IL

46

I

V

54

A

VT

71

G

SA

73

V

I

77

V

AFTS

82

I

V

84

L

M

90

RTVFIRV

10 20 32

L

F

33 36 46

VL

54 71 77 82 84 90

APVFIRV

10 32 46

I

V

47

I

V

50

LVM

54 73 84 90

LPV/r 10 20 24 32 33 46 47 50

F

L

53

VL

54

L

P

63 71 73

AFTS

82 84 90

Primary

Secondary

Undetermined Significance

©Lab21 May 2012

Bloor. Antivir Ther 2000;5(suppl 3):132.

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

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

EGFR Pathways and Drug Targeting

©Lab21 May 2012

Iressa analysis in NSCLC by EGFR status

©Lab21 May 2012

Analysis of CRC response to EGFR inhibitors

EGFR Pathways and Drug Targeting

Kras Mutants

Kras wt/Braf Mutants

Kras wt/?

52%?

©Lab21 May 2012

38%Kras mut

14%Brafmut

Erbitux and Vectibix only effective in 10-20% of resistant metastatic colorectal cancer

Vemurafenib

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

PFS – 5.3 months vs 1.6 months

Rapid Response of Metastatic Melanoma

using Vemurafenib

©Lab21 May 2012

R&D Productivity is on the decline

0.1

1

10

100

1950 1980 2010

NMEs per $B R&D spent (inflation adjusted)

Source: Bernstein Research ―The Long View – R&D Productivity 2010)

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‖

Parallel Track Dx and Rx Development

Pharmaceutical

Dx Marker

Preclinical Phase 1 Phase II Phase III Launch

Discovery Validation Development Implementation RegulatoryRobustness Clinical ValidationReproducibility

Launch

©Lab21 May 2012

FDA Approval for VemurafenibOn 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 cancerSecond targeted therapy approved with a test this yearOn 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.

Current levels of drug performance are far from satisfactory

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”

“Today, the response rates vary from 20% to 75%, depending on the drug and the disease”

Jürgen Schwiezer

CEO, Roche

Pharmaceutical industry

Diagnostic industry

Health Regulators

The Emergence of Next-Generation Sequencing

Parallel Track Dx and Rx Development

Pharmaceutical

Dx Marker

Preclinical Phase 1 Phase II Phase III Launch

Discovery Validation Development Implementation RegulatoryRobustness Clinical ValidationReproducibility

Launch

©Lab21 May 2012

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

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 notthe 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)

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

US: Unequal Regulation of IVDs

FDA

IVD Manufacturer

FDA Enforcement Discretion

IVD Kit

CLIA Certified Lab

Laboratory Developed Test (LDT)

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

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