07-11-2008

1

Alterações

empresariais

sustentadas pelo

conceito de engenharia

do Produto

Patrício Soares da Silva,

MD, PhD

07-11-2008

2

Summary

The Cost of Drug Discovery and Development

• Average cost to discover and develop a new drug = $800 million

• Average length of time from discovery to patient = 10-15 years

• Only one NCE (new chemical entity) out of 10,000 Leads will make it to launch.

Target

Identification

and

Validation

Assay

Development

Lead

Generation

HypothesisGeneration

Candidate Development Commercialization

Phase3

Regis-tration

GlobalLaunch

LeadOptimization

FirstHuman

Dose

Phase1

Phase2

Current opportunity

New technologies have emerged

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3

Paradigm shift in R&D and medicine

Clinical definition of disease diagnosis Molecular definition diagnosis

and predisposition

Future challenge

Patient-tailored therapy

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4

Future challenge

Patient-tailored therapy

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5

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6

R&D

in

BIAL’s mission in R&D

Seek novel therapies

• Identify new biological targets for

pharmacological intervention

• Develop new medicines

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7

Main research areas

• SNC disorders

• Cardiovascular disorders

• Allergic disorders

Porto

Bilbao

BIAL Facilities - Portugal

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• 93 collaborators (21 PhD) from 7 nacionalities

• Contracts with 77 R&D institutions (1993-2008)

• > 10.000 NCEs (1993-2008)

• 6 new medicines

• € 30.000.000 R&D investment annually

BIAL’s R&D

Sourc

e:

Sites c

om

panie

s

2004

R&D

Investment in main Southern European

companies (% sales)

BIAL invests more than 20% of its sales in R&D projects

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9

R&D resources

Non-clinical research

• Medicinal chemistry & analytical chemistry

• Pharmacology, biochemistry, molecular and cellular biology, metabolism and pharmacocinetics

• Forlumation

Clinical research

• Human pharmacology

• Clinical pharmacology

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10

Medicinal Chemistry

Toxicology, Pharmacokinetics & Metabolism

Exploratory Pharmacology

LeadOptimization

PhaseI

PhaseII

PhaseIII

Productapproval

CandidateSelection & evaluation

LeadFinding

Bioanalysis

Molecular Informatics

Biochemistry & Molecular Biology

Scale-up Chem

TargetSelection

Research before treating patients

Production & purification of rS-COMT

COMT

Progression in purification

1 2 3 4

COMT

IPTG

U I

Dete

rmin

ati

on

of

iso

ele

ctr

ic p

oin

t

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11

Mol Pharmacol 62, 795-805, 2002

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Target selection

Mol Pharmacol 62, 795-805, 2002

CNS Drug Reviews, 13, 352–379, 2007

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13

Development of a structural model of human S-COMT

rat COMT

human COMT

Seq homology > 80%

Ramachandran

Structure overlay (active site)

3.0

4.0

5.0

6.0

7.0

3.0 4.0 5.0 6.0 7.0

pIC

50

exp

eri

me

nta

l

pIC50 predicted

SIMCA-P 11 - 05/11/30 11:45:36 AM

Development of novel drugs: QSAR predictive model

Training set: 32 compounds; Validation set: 13 compounds

PLS Model: 4 principal components, R2 = 0.96 , Q2 = 0.86

APPLICATION in DISCOVERY:

- Over 350 novel structures conceived in silico

- Circa 150 novel compounds synthesized at Bial

- in vitro potency: IC50 100 – 0.14 µM

Over 70 structure-based

electronic descriptors

plus

physico-chemical properties

Determinants of

enzyme interaction

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In silico Virtual Screening

- Chemical groups of interest

- Calculated Physico-chemical properties

- Predicted higher activity

> 600,000 chemicals

74 chemicals

selected for

procurement

and

biological testing

21 HITS

with more than 80%

in vitro enzime

inhibition

(28% success rate)

1 lead

compound

selected

Lead optimization program

> 300 new related structures

synthesized and tested

Pharmacological tests

Toxicity evaluation

Few excelent candidates

Search for new lead candidates (structure hopping)

Commercial

databases

N

SO

Cl

Cl

F

S S

NH

O

Cl

O

ClNO

O

O

Cl

Cl

N

NH

S

Cl

Cl

Cl

O

O

O

O

SNH

S

O

OO

Lead Finding & Assay development

Tissuehomogenates

Tissue culture

In vivo

Chemicallibrary

NHN

N

O

O

OH

S

NN

O

O

OLeads

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15

A B C D E F G H I J K L M N O

0

25

50

75

100

Rem

ain

ing

co

mp

ou

nd

(%

)

Lead Optimization

C28

528

628

728

828

929

029

129

229

329

429

529

629

729

829

930

030

130

230

330

430

530

630

730

8

0

25

50

75

100

125%

C

Enzyme activity in cell lines

O

OH

OH

N+

O-

O

-8 -7 -6 -5

0

25

50

75

100

125

Log [Compound] (M)

En

zym

e

acti

vit

y

(% o

f co

ntr

ol)

IC50 in homogenates

Metabolic stability in microsomes

Transport studiesin Caco-2

Candidate

Candidate evaluation

BIA 3-202

0 6 12 18 24

0

5

10

2535455565

Time (h)

µg/m

l

BIA 3-476

0 6 12 18 24

0

5

10

15

Time (h)

µg/m

l

BIA 3-270

0 6 12 18 24

0

1

2

3

4

5

Time (h)

µg/m

l

BIA 3-465

0 6 12 18 24

0

5

10

15

Time (h)

µg

/ml

metabolic profile

Pharmacokinetic peofile

CNS

endocrine

cardiovascular

respiratoryrenal

acute toxicityembryotoxicity

Carcinogenicity

chronic toxicity

MTD

rodents, dog, rabbitnon-human primates, minipig,

gastrointestinal

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16

BIAL pipeline

Antiepileptic Eslicarbazepine Acetate – Zebinix® *

Development timeline

* proposed EU trade name.

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BIAL in the WorldBIAL is active in more than 30 locations in 4

continents.

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PortugalTop 10 Pharmaceutical Companies

Portugal

Market Share of BIAL Main Products

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PortugalBIAL Main Therapeutic Areas

BIAL Group - Sales/Revenue - 1998/2008

07-11-2008

20

Alterações

empresariais

sustentadas pelo

conceito de engenharia

do Produto

Patrício Soares da Silva,

MD, PhD