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Understanding the
Research and
Development Process
Edward W. Holmes, MD
President Sanford Consortium
Nov. 20, 2014
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Making a Novel Drug is Very Hard
Science and Medicine Challenging
Expensive
Lengthy Time Process
High Risk of Failure
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Making a Novel Drug is Much Like Rocket Science
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Landing Philae on 67p Comet
Robot Design; Target Identification
Took > 10 years
Cost $ 1.8 Billion
Team of Skilled Scientists
Odds of Success < 1/10000
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Making a Novel Drug
Drug Design; Target Identification
Takes 10-15 years
Costs $ 1.5-2.0 Billion
Team of Skilled Scientists
Odds of Success: 1/5000/molecule
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From Discovery to Delivery
Lead
Lead
Optimization
Drug
Target Lead Lead
Optimiz-
ation
Target
Validat-ion
GMP Clinical
Trials
Clinical
Delivery
The Enablers
Discovery
Research
High Throughput
and Design
Medicinal
Chemistry
Models: Mice
Primates
Manufacturing Patients G l o b a l
H e a l t h
Ph.D.
MD Industry
Chemist
Translational Ph.D.
Physician-Scientist
Physician
Scientist Clinical
Investigator Clinicians
The Human Capital
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BIOCHEMISTRY PATHOLOGY
GENOMICS
TRANSGENIC ANIMALS
IMAGING
ANIMAL MODELS
EPIDEMIOLOGY
CELL BIOLOGY PATHOPHYSIOLOGY
OF DISEASE
THERAPEUTIC TARGET
STRUCTURAL BIOLOGY
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Drug Discovery and Development is Time
Consuming
Pre-Clinical R&D: 1-6 years
Clinical Testing: 6-11 years
FDA Approval: 1-2 years
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FDA Approval of New Molecular Entities over Last
10 Years
Average: 26 per year
Range: 18-36 per year
2013: 27 NMEs
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Most New Drugs are Not
Novel Therapeutics
60-70 percent of new drugs
approved by the FDA are me-
too drugs; they are not “first in
class”
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Why Develop Me-Too Drugs ?
• Not profit
• Not market share
• The Target has been Validated
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Why is Failure Rate so High for Novel Drugs
Not Safe
Not Effective
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Reasons for Failure in Development of
Novel Therapeutics
• Lack of Efficacy - 46%
• Adverse Effects in Man – 16%
• Animal Toxicity – 17 %
• Pharmacokinetics – 7%
• Commercial and other – 14 %
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Mice are NOT Humans: Efficacy of Target Only Validated at POC
Stage In Humans
Further Characterization Small Molecule Screen
Chemical Probe Development
Chemistry Optimization
Phase III-IV
Clinical Studies
Phase I-II
Clinical Studies
FDA Approval
FDA IND
Submission
Preclinical
Toxicology
Validation
Mouse Model
R01 - P01
IRB
Approval
Basic
Discovery
16
Image: Elizabeth Nabel, M.D., Partners Research Retreat 3/2010
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Making a Novel Drug
Drug Design; Target Identification
Takes 10-15 years
Costs $ 1.5-2.0 Billion
Team of Skilled Scientists
Odds of Success: 1/5000/molecule
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Public and Private R&D Enterprise in 2010
NIH: $ 31 Billion
US Pharma: $ 41 Billion
US Biotech: $ 17 Billion
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Changes in Biomedical Research Landscape
Pharma Outsourcing R&D
Academia Partnering with Pharma
Pharma Concentrating more on Development
Biotech Assuming Risks of Upstream Research
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Public Private Partnerships: New Models are Emerging
Consortia Bringing Together Institutions and Expertise
Academic Collaboration Replacing
Contract Research with Pharma
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Collaborating Organizations
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•7.5 acre site •Proximal to all Participating Organizations
•52 year Ground Lease •$1/year
Project Site
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San Diego Biotech
3rd largest biotechnology sector in nation 500 companies
36,000 employees
$8.5 billion annual economic impact (SANDAG)
$901 million VC investment in 2006 (E&Y/Dow Jones Venture
On)
• its ‘biotechnology innovation pipeline’ and
• its success in bringing ideas to the marketplace and
creating companies, jobs and products.
Source: Milken Institute Report, “America’s Biotech and Life Science Clusters”
San Diego is highest ranked biotech and life
science cluster in the nation, measured by:
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Public Private Partnerships: New Models are Emerging
Academic Collaboration Replacing Contract Research with Pharma
Consortia Bringing Together Institutions and Expertise
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PPP Research Collaborations
Joint Funding: Shared Risks-Shared Rewards
Academic & Industrial Investigators Work as Team
Joint Steering Committees Oversee Research
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NYC: Takeda Translational Medicine Hub
Joint Funding: Pharma, philanthropy, government, institution
Basic and Clinical Investigators from AMCs and Takeda co-Located for Optimal Collaboration
Joint Steering Committee Selects Projects and Reviews Progress
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Industrial Partnership Office
Single Site of Contact for Group of Public Research Institutions
Coordination of Contracting with Multiple Institutions
Business Development Expertise for Multiple Institutions
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Holy Grail: Better Target Identification
Inhibition/Stimulation of Drug Target that Will Produce the Desired Effect with Minimal Toxicity
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Personalized/Precision Medicines
The correct drug for the correct patient
More effective; less toxicity
Smaller, quicker, cheaper clinical trials
Challenge: Defining Molecular Basis of Disease
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Personalized/Precision Medicines
Gleevac-Chronic Myelogenous Leukemia: BCR-ABL Oncogene
Herceptin-Breast Cancer: Monoclonal Antibody to EGF Receptor
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Cost Benefit Tradeoffs
Solvaldi-Hepatitis C
One pill cost $1,000; 12 week
course of therapy cost $84,000
> 80% cure rate
? Less expensive than long term cost of liver failure and liver cancer
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Drug Discovery and Development Going Forward Need better target identification
Need faster, better, cheaper
clinical validation
Need continued investment in basic and clinical science
Need understanding of complexity in R&D of novel therapeutics
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Changing Landscape of Therapeutics
No longer just small molecules
Biologics are Here: Peptides and Monoclonal Antibodies
Cell Therapies are on the way: Gene Therapy and Stem Cells
Subcellular Particles ?: Exosomes
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Potential of Gene Therapy and Stem Cell Therapy
Gene Modification of T Cells-Chronic Lymphocytic Leukemia
Stem Cells that make Insulin-Type I Diabetes