Drug Development – a new way forward?

Dr Ian BarwickBusiness Development Manager

Systems Biology Ireland, UCD

Overview

• Background to drug development• Current performance• Issues• The way forward?

– Systems approaches– Personalized medicine

• Current work

Background

• Drug development is expensive, risky and with no guarantee of clinical or financial success

• We still don’t fully understand many of the diseases that affect us

• Probably half of all medicines prescribed do not work in patients

Drug Development Process

Lead GenerationDiscoveryChemical Synthesis Scale-upFormulation DevelopmentSafety TestingPhase I TrialsPhase II TrialsPhase III TrialsNew Drug ApplicationProduct Approval

10 - 15 years

Current Performance

Decline in R&D Productivity

Data for PWC – Pharma 2020: Virtual R&D

Drug Development Statistics• Developing a new medicine takes an average of 10–15 years; the

Congressional Budget Office reports that “relatively few drugs survive the clinical trial process”

INDEFINITE

Drug Discovery Preclinical Clinical Trials FDA Review Scale-Up to Mfg. Post-MarketingSurveillance

ONE FDA-APPROVED

DRUG

0.5 – 2 YEARS6 – 7 YEARS3 – 6 YEARS

NUMBER OF VOLUNTEERS

PHASE 1 PHASE 2 PHASE 3

5250~ 5,000 – 10,000

COMPOUNDS

PRE-

DIS

COVE

RY

20–100 100–500 1,000–5,000

IND

SUBM

ITTE

D

NDA

SU

BMIT

TED

Drug Development Costs Increased

1979 1991 2000 2005$0.0

$0.2

$0.4

$0.6

$0.8

$1.0

$1.2

$1.4

$100M

$300M

$800M

$1.3B

Billi

ons

(Con

stan

t Dol

lars

, Yea

r 200

0)

Sources: 1J. DiMasi and H. Grabowski, "The Cost of Biopharmaceutical R&D: Is Biotech Different?," Managerial and Decision Economics, 2007; J. DiMasi et al., “The Price of Innovation: New Estimates of Drug Development Costs,” Journal of Health Economics, 2003.

Patent Cliff

Chronic Disease Projections (US)

1995 2000 2005 2010 2015 2020 2025 20300

20

40

60

80

100

120

140

160

180

200

45.4%46.2%

47.0%48.3%

48.8%

47.7%

49.2%

Num

ber

of

People

wit

h

Chro

nic

Condit

ions

(mill

ions)

Year

44.7%

In the US, every 30 seconds, a lower limb is amputate as a consequence of diabetes

Medicine Approvals for Rare Diseases

1970's 1983-1996 1997-20100

40

80

120

160

200

10

145

202

Rare diseases are those that affect 200,000 or fewer people in the U.S. There are between 6,000 and 7,000 rare diseases affecting 25 million Americans.

The Orphan Drug Act (ODA) was passed in 1983 to encourage the research and development of medicines to treat rare diseases. Since then, the FDA has approved more than 200 medicines for rare diseases.

Num

ber

of

Dru

gs

Appro

ved f

or

Orp

han D

isease

s

The Way Forward

Systems Approaches

Systems Biology Ireland• Systems Biology Ireland (based at University College Dublin) is a highly

interdisciplinary, research driven centre that combines expertise in computing, mathematics, engineering, chemistry, biochemistry and biology to address key questions in biology & biomedicine.

• It focuses on Growth factor receptor signalling• Cell fate decisions in adult stem cells• Cell motility and migration• Hypoxia signalling

• Works out how we are wired together

Understanding the emergent properties of biochemical networks• How do biochemical networks specify biological decisions?• How does the network design determine functions?• How can we manipulate these networks ?

Integrated approach• Mathematical, computational & statistical modelling • Advanced imaging• Omics technologies• Cell & molecular biology• Biochemistry

Systems Biology Ireland

Systems Biology Ireland Research Areas

Application Areas

Improved MSCs for therapy

Cancer & inflammatory diseases

New drug targets & rational drug combinations

Predictive models of disease mechanisms

Outcomes

High throughput

perturbationProteomics Imaging Microfluidics

Gene Arrays &Sequencing

Computational modelling

Technologies

Systems Biology Ireland

Pathway Description:The MAPK/Erk signaling cascade is activated by a wide variety of receptors involved in growth and differentiation including receptor tyrosine kinases (RTKs), integrins, and ion channels. The specific components of the cascade vary greatly among different stimuli, but the architecture of the pathway usually includes a set of adaptors (Shc, GRB2, Crk, etc.) linking the receptor to a guanine nucleotide exchange factor (SOS, C3G, etc.) transducing the signal to small GTP binding proteins (Ras, Rap1), which in turn activate the core unit of the cascade composed of a MAPKKK (Raf), a MAPKK (MEK1/2), and MAPK (Erk). An activated Erk dimer can regulate targets in the cytosol and also translocate to the nucleus where it phosphorylates a variety of transcription factors regulating gene expression.

MAPK/Erk in in Growth & Differentiation

Too much data?

• With the rise in experimental techniques and instrumentation masses of data are being generated

Data

Knowledge

Development Roadmap

Simple Organisms

Advances in Basic Concepts in

Biology

Humans

Disease Models

Systems Biology

Development Roadmap

New Diagnostics

Disease Models

• Diagnostics• Biomarkers• Clinical Screening• Prevention• Wellness

New Targets

New Treatments

Personalized Medicine

• Reduced Animal Testing• Patient Stratification• Modelled Clinical Trials

Pharmaceutical Industry Drivers• Increased R&D Spend• Increased generics competition• Reduced Drug Approval Rates• Patent Cliff• Reduced Revenue Streams• Reduced uptake by healthcare providers

Current Work

Work in Progress - background

• Previous work on ALC-01 new ‘protein’ wide spread affects on human health (dizzyness, nausea, memory-loss etc)

[Carlsberg A., Guinness A., Daniels, J. - J of Irreproducible Results 2010]

• Recent work on elucidating the structure revealed hydroxylated form

• Renamed ‘protein’ ALC-OH-01 – many isomers!

• Wanted to look at the this effect in more detail

Hypothesis investigated

The number of CHAOTIC delegates in the bar area related to concentrations of the ALC-OH-01 protein

- d [AD] proportional d[ALC-OH-01]B – d[ALC-OH-01]C

dT dT dT

[CHAOTIC] = concentration of CHAOTIC delegates in the bar[ALC-OH-01]B = concentration of ALC-OH-01 Bought

[ALC-OH-01]C = concentration of ALC-OH-01 Consumed

Model Predicts [C

HAO

TIC]

Time

Significant ‘noise’ due to Very Unsteady State Kinetics

CHAOTIC Plateau

Paper will be submitted shortly

Hatt End Point

Systems Medicine Conferenece10-13 September, Dublin