Discovering Drugs: the Future of GSK
Peter Goodfellow Senior Vice-President Discovery Research GSK R&D
Issues for the Pharmaceutical Industry
• Rapid escalation of the costs of R&D • Higher risks of failure associated
with greater innovation
• Global tightening of regulatory
policy
• Diminishing advantages of being
first to market
2
Pharmaceutical Industry Productivity
300 Indexed R&D Expenditure/Sales/NME Output (1989=100) 275
R&D Expenditure
250 225 200 175 150 125 100 75 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 Year
New Drug Output
: CMR International based on data collected from 55 pharmaceutical companies and 13 trade associations. Data presented includes R&D expenditure and output from traditional pharmaceutical as well as the biotech industry
A Strategy for Success
• Short term (1-2 years)
– IN LICENSE – PLEs
• Medium term (3-5 years)
– CENTRES OF EXCELLENCE FOR DRUG DISCOVERY
• Long term (5-9 years)
– RE-ENGINEER DRUG DISCOVERY AND DEVELOPMENT
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A Strategy for Success
• Short term (1-2 years)
– IN LICENSE: >25 COMPOUNDS ACQUIRED – PLEs : EXTENDING EXSISTING FRANCHISES
• Medium term (3-5 years)
– CENTRES OF EXCELLENCE FOR DRUG DISCOVERY (CEDD)
• Long term (5-9 years)
– RE-ENGINEER DRUG DISCOVERY AND DEVELOPMENT
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GSK In-Licensing
Biovail Bayer Scios Adolor Gilead Roche Elbion Merck KGaA Sepsicure Biovitrum AB Shionogi JV Neurocrine Nobex Theravance Inex Exelixis Kissei 3M Bayer Cytokinetics Tanabe Unigene Ono Wellbutrin once daily Levitra nesiritide (in EU) Alvimopan adefovir dipivoxil (in RoW) Ibandronate PDE IV inhibitors SSRI/5HT1a partial agonist Endotoxin binder 5-HT 2C receptor agonists 4 new compounds CRF receptor antagonists Oral insulin analogue (HIM2) Long-acting ß-agonists Liposomal encapsulated Hycamtin Vascular biology, inflam. & oncology Oral anti-diabetic agents Respiratory drug formulation PPAR gamma modulators Mitotic kinesin inhibitors Several new compounds Oral PTH CCR5 receptor antagonists Depression Male erectile dysfunction Acute heart failure Postoperative ileus Hepatitis B Osteoporosis Rhinitis, Asthma, COPD Depression Sepsis Obesity, others HIV, Stroke, Alzheimer’s Anxiety, Depression Type 2 diabetes Asthma & COPD Cancer Various Diabetes Asthma/COPD Osteoporosis, others Cancer Various Osteoporosis HIV Filed Filed Filed Phase III Phase III Phase III Phase II/I Phase II Phase II Phase II Phase II/I Phase I Phase I Phase I Pre-clinical Pre-clinical Pre-clinical Pre-clinical Pre-clinical Pre-clinical Pre-clinical Pre-clinical Pre-clinical
Key PLE Launches
Trizivir Coreg (SHF) Augmentin ES Paxil (GAD & PTSD) Twinrix (v) Infanrix Penta (v) Augmentin XR Avandamet Paxil CR Lamictal Bipolar Dep Advair Pediatric Advair COPD Advair once daily Wellbutrin XL (once daily) Pediarix (v) Paxil CR (PMDD) Valtrex - Prevent Herpes Transm Coreg (Post MI) ReQuip restless leg Hycamtin SCLC Ziagen/Epivir
2001
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2002
2003 - 2004
A Strategy for Success
• Short term (1-2 years)
– IN LICENSE: >25 COMPOUNDS ACQUIRED – PLEs : EXTENDING EXSISTING FRANCHISES
• Medium term (3-5 years)
– CEDD: SIGNIFICANT INCREASE IN PRODUCTIVITY
• Long term (5 plus years)
– RE-ENGINEER DRUG DISCOVERY AND DEVELOPMENT
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The R&D Process
Discovery
Target Lead
Development
Candidate FTIH
Market
Launch Products of Value
PoC
Phase File & approval III
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GSK R&D Organisation
Genetics Research Centres of Excellence Discovery Research for Drug Discovery Pre-clinical Development New Product Development
GR DR
CEDDs
PCD NPD
Target
Lead
Candidate FTIH
PoC
Phase File & approval III
Launch
Products of Value
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Centre of Excellence in Drug Discovery
• A group of 250-350 scientists under a single line
management.
• A co-located group, specialised in a single
therapeutic area or collection of diseases.
• Skills include ‘lead optimisation’ chemistry,
‘disease-specific’ biology, pre-clinical and clinical expertise.
• Devolved decision making and accountability
CEDD Productivity
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Clinical Pipeline - 123 Projects
Number of Projects
30 24
NCEs & vaccines by Phase
23 57
21 20
12 10
43
10 6 7
0
NCEs NCEs
PLEs PLEs
Vaccines Vaccines
Phase I
Phase II
Phase III + Registration
GSK Product Development Pipeline at October 2002
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GSK R&D as the machine to play others’ music ...
Internal CEDDs
Cytokinetics
GR DR
Shionogi Tanabe Exelixis
PCD NPD
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A Strategy for Success
• Short term (1-2 years)
– IN LICENSE: >25 COMPOUNDS ACQUIRED – PLEs : EXTENDING EXSISTING FRANCHISES
• Medium term (3-5 years)
– CEDD: SIGNIFICANT INCREASE IN PRODUCTIVITY
• Long term (5-9 years)
– RE-ENGINEER DRUG DISCOVERY AND DEVELOPMENT
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Transforming Drug Discovery • Increase predictability and decrease
attrition • Exploit new technologies e.g. genomics and genetics • Automate where possible
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Transforming Drug Discovery • Increase predictability and decrease
attrition: systems science • Exploit and integrate new technologies eg genomics and genetics, • Automate
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Systems Science
• Targets in some target classes are more amenable to
intervention by small molecules
• Information from one member of a target class informs
decisions about other members of that class
• Strategies can be applied to all members of the class
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2000 tractable Drug Targets
• 400 G protein coupled receptors (GPCRs) • ~450 proteases • >400 kinases Biochemical Classes of Drug Targets of Current Therapies (N=483) • ~250 ion channels Enzyme • 42 nuclear receptors Unknown GPCR Ion Channel • 22 integrins
Hormone NR
Drews (2000) Science 287:1960-1964
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Drugs targeting GPCRs
Receptor
Histamine Serotonin H2 H1 5HT 1B/1D 5HT 1A 5HT 2 5HT 4 mixed AT1 βmixed β1 β2 α β1 /β2/α1
Drug
Zantac, Tagamet Claritin Imigran Buspar Zyprexa Prepulsic Leponex Cozaar, Teveten Timuptol, Inderal Tenormin Cerevent, Ventolin Cardura Coreg Atrovent Requip Cytotec
Disease
Ulcers Allergies Migraine Anxiety Psychosis Nocturnal heartburn Schizophrenia Hypertension Glaucoma/Hypertension Hypertension Asthma Prostate hypertrophy Congestive heart failure COPD Parkinson's Ulcers
Angiotensin Adrenergic
Muscarinic Dopamine Prostaglandin
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Orphan GPCR ‘target validation’
In silico mRNA expression pattern Cloning Receptor expression
-- -
--
Immunohisto chemistry
Knock-outs
Screening: Natural Ligands/ Focused Sets/HTS
Ligand
No Ligand Overexpression
Target Validation In vitro / in vivo models
Orphan receptor screening strategy
In silico Tissue expression pattern Family tree analysis
---------- ---
Mammalian Expression (+ promiscuous G-proteins)
Ca2+ assay (FLIPR)
Putative Ligands
Activating Ligand Detailed expression profile KO model 22 Biological evaluation
Orphan receptors paired with ligands at GSK
• • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • •
CRLR (CGRP) CRLR (CGRP) AZ3B (C3a) AZ3B (C3a) HFGAN72 (Orexin 1) HFGAN72 (Orexin 1) HFGANP (Orexin 2) HFGANP (Orexin 2) 11CBy (MCH) 11CBy (MCH) GPR14 (Urotensin II )) GPR14 (Urotensin II HMTMF81 (LTD4) HMTMF81 (LTD4) EDG1 (S1P) EDG1 (S1P) KIAA0001 (UDP-glucose )) KIAA0001 (UDP-glucose HLWAR77 (NPFF/AF) HLWAR77 (NPFF/AF) HNEAA81 (A4/A5/A6PA )) HNEAA81 (A4/A5/A6PA HOFNH30/EDG7 (LPA) HOFNH30/EDG7 (LPA) AXOR 21 (MCH) AXOR 21 (MCH) HNFDL69/EDG6 (S-1-P) HNFDL69/EDG6 (S-1-P) Axor29/EDG8 (S-1-P) Axor29/EDG8 (S-1-P) Axor35 (Histamine) Axor35 (Histamine) FM-3 (NmU) FM-3 (NmU) Axor34 (NmU) Axor34 (NmU) Several others not yet in public domain Several others not yet in public domain
• • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • •
GPR10 (Prolactin releasing peptide) GPR10 (Prolactin releasing peptide) APJ (Apelin) APJ (Apelin) GPR16 + JULF4 (LTB4) GPR16 + JULF4 (LTB4) ORL-1 (Nociceptin )) ORL-1 (Nociceptin EDG3,5 (S1P) EDG3,5 (S1P) EDG2,4 (LPA) EDG2,4 (LPA) H3 H3 GPR38 (Motilin) GPR38 (Motilin) OGR-1 (SPC) OGR-1 (SPC) NPFF-1/B5 NPFF-1/B5 HG57/Axor54 (LTD4) HG57/Axor54 (LTD4) Axor12 (KiSS-1) Axor12 (KiSS-1) P2T (ADP) P2T (ADP) CRTH2 (PGD2) CRTH2 (PGD2) TA1 (Tyramine) TA1 (Tyramine) TDAG8 (Psychosine) TDAG8 (Psychosine) G2A (LysoPC) G2A (LysoPC) GPR4 (SPC) GPR4 (SPC)
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Transforming Drug Discovery
• Increase predictability and decrease
attrition: systems science • Exploit and integrate new technologies eg genomics and genetics • Automate
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Transforming Drug Discovery
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Transforming Drug Discovery
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Abacavir Hypersensitivity and HLA-B57
Cases HLA-B57+ 28 HLA-B57- 26 54
Controls 3 89 92 31 115
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Transforming Drug Discovery
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Automation
• Automation is ‘an’ enabler of our scientific
strategy - if we make more of the right molecules we can make:
– More drugs – Faster – Cheaper
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Discovery Automation Facilities
• A large capital investment by GSK - >$300M over
three years
• Essential component of changing drug discovery
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A Screening Facility in Spain
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Automation Facilities
• Tres Cantos, Spain:
high throughput screening
• Harlow, UK: chemistry • Upper Providence, USA: chemistry and high
throughput screening
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High Throughput Screening in 2002
40 35
30 25 20 15 10 5 0
number of wells
22% reduction in
cost
number of wells
2001
2002
Automation drove a significant increase in molecular screening Automation drove a significant increase in molecular screening productivity: the result has been an increase in lead quality and a productivity: the result has been an increase in lead quality and a decrease in the cost per well decrease in the cost per well
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Cost per screening well
millions of wells
Discovery Automation Facilities
• A large capital investment by GSK - >$300M
over three years
• Essential component of changing drug
discovery
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Improving Quality of Lead Compounds
Average IC50
– – – – 1996 2000 2001 2002 - 3000nM - 270nM - 75nM - 10nM
IC50 = a measure of potency (concentration required to inhibit 50%). The smaller the number the more potent the molecule.
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Improving cycle times
Time from first screen to candidate selection
TIME (years)
Industry Average
HCV polymerase inhibitor Urotensin-II receptor antagonist Vanilloid receptor antagonist
5-6 2 1/4
3 1/4
3
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Buildings, equipment and automation will not transform drug discovery without creative, motivated SCIENTISTS with a clear vision for how to use the new facilities.
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