1

Understanding the

Research and

Development Process

Edward W. Holmes, MD

President Sanford Consortium

Nov. 20, 2014

Making a Novel Drug is Very Hard

Science and Medicine Challenging

Expensive

Lengthy Time Process

High Risk of Failure

Making a Novel Drug is Much Like Rocket Science

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

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

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

BIOCHEMISTRY PATHOLOGY

GENOMICS

TRANSGENIC ANIMALS

IMAGING

ANIMAL MODELS

EPIDEMIOLOGY

CELL BIOLOGY PATHOPHYSIOLOGY

OF DISEASE

THERAPEUTIC TARGET

STRUCTURAL BIOLOGY

Drug Discovery and Development is Time

Consuming

Pre-Clinical R&D: 1-6 years

Clinical Testing: 6-11 years

FDA Approval: 1-2 years

FDA Approval of New Molecular Entities over Last

10 Years

Average: 26 per year

Range: 18-36 per year

2013: 27 NMEs

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”

Why Develop Me-Too Drugs ?

• Not profit

• Not market share

• The Target has been Validated

Why is Failure Rate so High for Novel Drugs

Not Safe

Not Effective

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 %

16

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

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

Public and Private R&D Enterprise in 2010

NIH: $ 31 Billion

US Pharma: $ 41 Billion

US Biotech: $ 17 Billion

Changes in Biomedical Research Landscape

Pharma Outsourcing R&D

Academia Partnering with Pharma

Pharma Concentrating more on Development

Biotech Assuming Risks of Upstream Research

Public Private Partnerships: New Models are Emerging

Consortia Bringing Together Institutions and Expertise

Academic Collaboration Replacing

Contract Research with Pharma

Collaborating Organizations

•7.5 acre site •Proximal to all Participating Organizations

•52 year Ground Lease •$1/year

Project Site

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:

Public Private Partnerships: New Models are Emerging

Academic Collaboration Replacing Contract Research with Pharma

Consortia Bringing Together Institutions and Expertise

PPP Research Collaborations

Joint Funding: Shared Risks-Shared Rewards

Academic & Industrial Investigators Work as Team

Joint Steering Committees Oversee Research

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

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

Holy Grail: Better Target Identification

Inhibition/Stimulation of Drug Target that Will Produce the Desired Effect with Minimal Toxicity

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

Personalized/Precision Medicines

Gleevac-Chronic Myelogenous Leukemia: BCR-ABL Oncogene

Herceptin-Breast Cancer: Monoclonal Antibody to EGF Receptor

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

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

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

Potential of Gene Therapy and Stem Cell Therapy

Gene Modification of T Cells-Chronic Lymphocytic Leukemia

Stem Cells that make Insulin-Type I Diabetes