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New treatment
1.0 Comparator
0.6
0.4
0.2
0
0 6 12 18 24 30 36
Drug targeted to specific Patient identified through
oncogene or aberrant molecular profiling of Significant improvement
pathway driving the their tumor in survival
specific tumor
DRAFT – Subject to Further Review – Company Confidential and Proprietary – Internal Use Only
What Are the Issues in “Personalized medicine”
Development and Commercialization?
Clinical test validation of a new diagnostic for use in selecting drug therapy or avoiding
drug therapy should be characterized by studying the test in relation to the intended
clinical outcome in patient subgroups with and without the analyte of interest:
SOC + Drug
Mutant +
SOC + Placebo
Biomarker data
All Subjects
available
SOC + Drug
Mutant ‒
Issues SOC + Placebo
DRAFT – Subject to Further Review – Company Confidential and Proprietary – Internal Use Only
Futur State: Drug and Diagnostic Co-Development
Paradigm
IPASS trial experience: ability to gain molecular data in clinical trial setting
Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma; Mok et al, NEJM Sept 09
261
132
1217 437 Mutant +
129
Biomarker data
All Subjects
available
91
Mutant ‒
Issues 85
176
Future State:
Streamlined Ph 3 clinical trials focusing on target patient population
Adaptive and cross-over designs; acceptance of PFS as endpoint
Simultaneous approval of companion diagnostic
DRAFT – Subject to Further Review – Company Confidential and Proprietary – Internal Use Only
The Challenge of Developing Personalized Medicine
for Small Patient Populations
Number of
Tumor Type Molecular Event Rate Patients in US
ALK Mutation or
Neuroblastoma ~20-25% ~200 patients
Amplification
DRAFT – Subject to Further Review – Company Confidential and Proprietary – Internal Use Only
Case Study: Gefitinib – First EGFR Inhibitor to Gain
(and Lose, and Gain) Regulatory Approval
May 2003 Dec 2003 Sept 2008 April 2009
“All Comers” No New Patients Phenotypic Genotypic
Progression-Free Survival
1.0
Progression-Free Survival
1.0
Hazard ratio, 0.74 (95% CI, 0.65-0.85) Hazard ratio, 0.48 (95% CI, 0.36-0.64)
p<0.001 p<0.001
0.8 0.8
Probability of
Probability of
0.4 0.4
Gefitinib
Gefitinib Superior
Superior to
to Chemo
Chemo in
in EGFR
EGFR
Mutant
Mutant Population
Population
EGFR-Mutation – Negative
Progression-Free Survival
1.0
Hazard ratio, 2.85 (95% CI, 2.05-3.98)
0.8
p<0.001 Future State:
Probability of
Chemo
Chemo Superior
Superior to
to Gefitinib
Gefitinib in
in Mutation
Mutation
Negative Population
Negative Population
DRAFT – Subject to Further Review – Company Confidential and Proprietary – Internal Use Only
Potential Treatment Alogrithm for Advanced-Stage Non-
Small-Cell Lung Cancer: (Good Performance Status): 2012
Potential
Potential Treatment
Treatment Algorithm
Algorithm
ALK
ALK Fusion
Fusion ++ ve
ve EGFR
EGFR Mutation
Mutation Molecular ERCC1
ERCC1 Low
Low Molecular ERCC1
ERCC1 High
High
Molecular
Chemotherapy
Chemotherapy
ALK
ALK Inhibitor
Inhibitor EGFR
EGFR inhibitor
inhibitor TS
TS High
High TS
TS Low
Low (Nonplatinum)
(Nonplatinum)
Molecular
RRM1
RRM1 Low
Low RRM1
RRM1 High
High
Platinum/
Platinum/ Platinum/
Platinum/
Gemcitabine
Gemcitabine Platinum/Other
Platinum/Other ±± Pemetrexed
Pemetrexed ±±
(or
(or Other)
Other) ±± Bevacizumab
Bevacizumab or
or Bevacizumab
Bevacizumab or
or
Bevacizumab
Bevacizumab or or Cetuximab
Cetuximab Cetuximab
Cetuximab
Cetuximab
Cetuximab
DRAFT – Subject to Further Review – Company Confidential and Proprietary – Internal Use Only
The Issue of the Tissue
Future State:
Multi-plex tests to optimize data from limited tissue
Next generation and non-invasive tests
Clear regulatory path for approval
DRAFT – Subject to Further Review – Company Confidential and Proprietary – Internal Use Only
Impact of Personalized Medicine on Adjuvant therapy
for Breast Cancer : the impact of Her2 Mab
HERA Trial
100%
80%
60%
DFS (%)
40%
20%
0%
0 6 12 18 24 30 36
Months from Randomization
Trastuzumab + Chemotherapy
Chemotherapy alone (Control)
60%
DFS (%)
0% Optimizing Anti-HER2
treatment for Early BC
0 6 12 18 24 30 36
ECCO15/ESMO34 Sept 09
Months from Randomization
Trastuzumab + Chemotherapy
Chemotherapy alone
Pros Cons
development development
• May reduce Ph3 study size and • Cost and scope of molecular profiling
costs if end points achieved more
rapidly/more robust difference • May select wrong biomarker
e.g., EGFR vs k-ras
• Potential for greater clinical
benefit in targeted population • Many logistical issues e.g., tissue
availability, regulatory path
Pros Cons
DRAFT – Subject to Further Review – Company Confidential and Proprietary – Internal Use Only
Future opportunity for accelerated Drug Development
timelines?
DRAFT – Subject to Further Review – Company Confidential and Proprietary – Internal Use Only
Future opportunity to reduce ineffective healthcare
expenditure
DRAFT – Subject to Further Review – Company Confidential and Proprietary – Internal Use Only
Potential New Drug Discovery and Development
Paradigm in the Era of Personalized Medicine
• Target oncogenes correlated • Molecular guided strategy for • Routine use of Molecular
with malignant cell growth and clinical trial patient selection Diagnostics to Guide
metastasis – Trials in enriched populations treatment decisions
• “Roadmap” for development to accelerate POC and target • Optimized patient outcomes
higher response/survival and improved survival
teams for biomarkers and
patient selection • Focus on poor prognosis • Robust Value Proposition
patients not well served by
current treatments
• Co-development of Companion
Diagnostic
DRAFT – Subject to Further Review – Company Confidential and Proprietary – Internal Use Only