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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