Post on 07-Dec-2018
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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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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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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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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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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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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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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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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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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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
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Alterações
empresariais
sustentadas pelo
conceito de engenharia
do Produto
Patrício Soares da Silva,
MD, PhD