Ongoing developments reflect the explosion in the number of kinase inhibitors that have entered and are moving through clinical development: • A series of 6 bi-monthly updates will provide an up-to-date assessment of the kinase pipeline outlook. • Their collective sales exceeded $4 billion. • Three more kinase inhibitors have been approved in 2007 and others have moved into Phase III in 2008. Continued on next page Insight Pharma Reports, a division of Cambridge Healthtech Institute 250 First Avenue • Suite 300 • Needham, MA 02494 • 781-972-5444 • InsightPharmaReports.com Kinase Therapeutic Pipelines: An Assessment of Targets and Agents in Development by Peter Norman, PhD, MBA DECEMBER 2007 Expert assessment of the leading class of agents Expert Intelligence for Better Decisions Insight Pharma Reports 6 Bi-monthly Insight Updates Vol. 1, No. 2 October 2008 New activity for August 2008 – September 2008 PDF format by Mark Via PLUS
Transcript
Ongoing developments reflect the explosion in the number of kinase inhibitors that have entered and are moving through clinical development:
• A series of 6 bi-monthly updates will provide an up-to-date assessment of the kinase pipeline outlook.
• Their collective sales exceeded $4 billion.
• Three more kinase inhibitors have been approved in 2007 and others have moved into Phase III in 2008.
Continued on next page
Insight Pharma Reports, a division of Cambridge Healthtech Institute250 First Avenue • Suite 300 • Needham, MA 02494 • 781-972-5444 • InsightPharmaReports.com
Kinase Therapeutic Pipelines:An Assessment of Targets and Agents in Development
by Peter Norman, PhD, MBA
DECEMBER 2007
Expert assessment
of the leading class of agents
Expert Intel l igence for Better Decis ions
Insight Pharma Reports
6 Bi-monthly
Insight UpdatesVol. 1, No. 2 October 2008
New activity for August 2008 – September 2008
PDF format
by Mark Via
PLUS
Overview
About the Authors:Peter Norman, PhD, MBA,is a pharmaceutical consultant and analyst based in Burnham Beeches, near Windsor, England. He has written and presented widely on various aspects of respiratory disease, drug development, and on the analysis of diverse therapeutic markets. Dr. Norman has more than 20 years of experience in the pharmaceutical industry in both R&D and competitive intelligence. His publications include many reviews.Mark C. Via, an editor at CTB International Publishing, has more than 14 years of experience writing and editing for pharmaceutical trade publications. He holds a BA in history from Williams College. Mr. Via has authored previous Cambridge Healthtech reports, including Monoclonal Antibodies: Pipeline Analysis and Competitive Assessment (www.insightpharmareports.com/reports/2007/88_Monoclonal_Antibodies/overview.asp).
Tables and Figures
FiguresThe Human KinomeMitogen-Activated Protein Kinase Signaling
CascadesSelectivity Profiles of Staurosporine and
3 Marketed Protein Kinase InhibitorsGenetic SWOT Analysis for Kinase
InhibitorsLeading Oncology Franchises in 2006 and
Proportion of Revenues Derived from Kinase Inhibitors and Growth Factor Receptor Antibodies
Kinase Inhibitors in Development from the Major Pharmaceutical Companies
TablesAGC Family of Protein Kinases, Listed in
Order of Phylogenetic SimilarityCAMK Family of Protein Kinases, Listed
in Order of Phylogenetic Similarity
CMGC Family of Protein Kinases, Listed in Order of Phylogenetic Similarity
CK1 Family of Protein Kinases, Listed in Order of Phylogenetic Similarity
STE Family of Protein Kinases, Listed in Order of Phylogenetic Similarity
TK Family of Protein Kinases, Listed in Order of Phylogenetic Similarity
TKL Family of Protein Kinases, Listed in Order of Phylogenetic Similarity
Families of Atypical Protein Kinases2005 and 2006 Sales of Marketed Kinase
Inhibitors2005 and 2006 Sales of Marketed
Recombinant ProductsRecently Approved Drugs Targeting Protein
KinasesKinase Inhibitors in Phase III Studiesp38 MAP Kinase Inhibitors in Clinical
Development
MEK Inhibitors in Clinical DevelopmentPI3K Inhibitors in Clinical DevelopmentAkt Inhibitors in Clinical DevelopmentCell Cycle (CDK and Chk) Inhibitors in
Clinical DevelopmentAbl Inhibitors in Clinical DevelopmentAnti-angiogenic Kinase Inhibitors in Clinical
DevelopmentIGFR Inhibitors in Clinical DevelopmentEGFR and ErbB2 Inhibitors in Clinical Devel-
opmentFlt3 Inhibitors in Clinical DevelopmentInhibitors of Other Kinases in Phase II
Clinical DevelopmentAurora Kinase Inhibitors in Phase I StudiesRaf Kinase Inhibitors in Phase I StudiesPan-FGF Inhibitors in Phase I Clinical
DevelopmentOther Kinase Inhibitors in Phase I Studies
In addition to ongoing studies of approved kinase inhibitors seek-• ing line extensions, a further 11 are in Phase III studies.
More than 130 kinase inhibitors are reported to be in either Phase • I or Phase II clinical development, with 47 reported to be in Phase II studies.
Protein kinases constitute a large family of proteins that is now firmly established as a major class of drug targets for the pharmaceutical in-dustry. The sequencing of the human genome has led to the identifica-tion of 518 protein kinases encoded within it—the human kinome. This constitutes one of the largest and most druggable classes of targets for the pharmaceutical industry, with the number of kinases exceed-ing the number of G protein—coupled receptors in the human genome.
An essential report for industry professionals working in R&D, portfolio management, and ki-nase product management, Kinase Therapeutic Pipe-lines: An Assessment of Tar-gets and Agents in Develop-ment and updated to October 2008 by the second of 6 bi-monthly supplements, reviews the consid erable array of drug devel-opment efforts directed at kinases and:
Provides profiles of the activities of the major companies as well • as the kinase inhibitors in development, and some of the specialist companies active in the field
Assesses the potential impact of the more advanced kinase inhibi-• tors, which offer significant market potential
Discusses some of the technical challenges faced in developing • such inhibitors
Concludes with commentaries from leading experts in the field•
With so many inhibitors reported to be in clinical development and many more in preclinical development, kinase inhibitors now make up a significant fraction of most major pharmaceutical companies’ pipelines, as well as an area of focus for many biotechnology com-
panies. The increased interest in this class of targets reflects both advances in identifying selective protein kinase inhibitors and a growing perception that these drugs offer a novel, well-tolerated oral therapy in some of the most untreatable cancers.
Although direct kinase inhibitors accounted for only 7% of the value of the oncology market in 2006, their increasing availabil-ity and use is likely to be one of the major drivers of growth in this market.
The number of kinase inhibitors in clinical development ensures that during the next 10 years a significant number of such agents
will reach the market. The majority of these will be for oncology in-dications, reflecting the more acute nature of the disease, and thus greater tolerability of potential side effects, and the current emphasis on developing kinase inhibitors for cancer indications.
Human KinomeTHE
TKLTK
STE
CMGC
SCYL2SCYL1SCYL3
OSR1
STLK3
STRAD/STLK5
STLK6
TAO3
LOKSLK
NIK
GCN2~b
TAO2TAO1
PAK1
PBK
ERK7
ERK3ERK4
CDKL5
ICKMAK
NLK
CDKL1CDKL4
CDKL2CDKL3
ERK2/p42MAPK
ERK1/p44MAPK
MOK
SgK071
CLIK1LCLIK1
TTKKIS
IRE1IRE2 TBCK
HRI
GCN2
CDC7
MAP3K4
KHS1KHS2
NRK/ZC4
MYO3B
MST1MST2
TNIK/ZC2
MINK/ZC3
MAP3K8
MEKK6/MAP3K6
RIPK3
LIMK2 TESK1TESK2
ALK2
TGFβR2
RIPK2
HH498TAK1
ARaf
KSR KSR2
BMPR1BALK7
ActR2ActR2B
ANKRD3 SgK288
ZAK
ALK4
DLKLZK
MLK2
MLK1
MLK3
LRRK1LRRK2
SgK496
RIPK1
WNK3
WNK2NRBP1 NRBP2
MEKK1/MAP3K1
MEKK2/MAP3K2
ASK/MAP3K5
MAP3K7
MLKL
SgK307
SgK424
HSER
ANPβ/NPR2
IRAK1IRAK3
SuRTK106
MOS
Lmr1Lmr2
Lmr3
Etk/BMX
ITK
BLK
EphA8
TECTXK
HCK
EphA7
EphA6
EphB3
EphA4
EphB1EphA5
EphA10
EphB6FRK
Srm
CSK
CCK4/PTK7
DDR1DDR2
MuSK
MetRon
IRR
ROR1
Tnk1
HER3Jak3
PYK2/FAK2
RYK
AckJak1
Tyk2Jak2
HPK1GCK
MST3
YSK1
SgK269
PRP4
SRPK2
HIPK4
CLK3
CLK4
CLK2CLK1
MSSK1
SRPK1
DYRK1B
DYRK4
HIPK3
DYRK2DYRK3
PAK3
Tpl2/COT
p38γ
MYO3A
MST4
HGK/ZC1
LIMK1
ALK1
MISR2BMPR2
ILK BMPR1A
BRafC-Raf/Raf1 TGFβR1
MLK4
WNK1
WNK4
MEKK3/MAP3K3
IRAK4
IRAK2
EphA2
EphA1Zap70/SRKSyk
FAK
PINK1
GSK3αGSK3β
ERK5
CK2α2CK2α1
RNAseL
PKRPERK/PEK
GUCY2D
GUCY2F
ANPα/NPR1Jak1~b
Tyk2~bJak2~bJak3~b
BTK
FgrLck
FynLyn
SrcYes EphB4
EphB2
EphA3
Fer
Brk
AblAbl2/Arg
CTK
FLT4
FLT3AxlMer
FLT1/VEGFR1
ALKLTK
IGF1RInsR
TrkA
FGFR2
EGFR HER2/ErbB2
HER4
KDR/VEGFR2Fms/CSFRKit
FGFR3
FGFR1FGFR4
PDGFRβPDGFRα
TrkB
TrkC
Tyro3/Sky
Ret
Ros
ROR2
Tie1Tie2
Fes
DYRK1A
HIPK1
HIPK2
Partial illustration of “The Human Kinome” Source: Cell Signaling Technology (www.cellsignal.com)
To order a report, e-mail [email protected], call Rose LaRaia at 781-972-5444, or order on-line
Chapter 1: Kinases1.1. The Function of Kinases1.2. The Human Kinome1.3. Kinase ClassificationAGC FamilyAMK FamilyCMGC FamilyCK1 FamilySTE FamilyTK FamilyTKL FamilyAtypical Protein Kinases1.4. Kinase Structure1.5. Kinases as Drug Targets
Chapter 2: Current Commercial Successes
2.1. Small-Molecule Kinase Inhibitors
GleevecIressa and TarcevaNexavarSutentRapamune and Certican2.2. Biological Agents
Chapter 3: Indications for the Use of Kinase Inhibitors
3.1. Cancer3.2. Angiogenic Conditions3.3. Inflammatory Diseases3.4. Metabolic Disorders3.5. Central Nervous
System Conditions3.6. Cardiovascular
Disease
Chapter 4: Strategies for Developing Kinase Inhibitors
AbbottAmgenAstraZenecaBayer ScheringBoehringer IngelheimBristol-Myers SquibbDaiichi SankyoEli LillyGlaxoSmithKlineJohnson & JohnsonMerck & Co.Merck SeronoNovartisPfizerRocheSanofi-aventisSchering-PloughTakedaWyeth5.2. Popular Targets5.3. Drugs Targeting Protein
Kinases that Have Recently Been Approved or Are Awaiting Approval
LapatinibNilotinibDasatinibSunitinibSorafenibPanitumumab5.4. Kinase Inhibitors in
Phase IIIMotesanibPazopanibAfliberceptVandetanibCediranibBIBW-2992Enzastaurin and RuboxistaurinDeforolimusLestaurtinibAlvocidib5.5. Kinase Inhibitors in
Chapter 7: Expert Interviews: A Virtual Roundtable
Stephen Burley, MD, DPhil, SGX Pharmaceuticals
Jose Duca, PhD, Schering-Plough Research Institute
David Hayes, PhD, MilliporeAlcide Barberis, PhD,
Oncalis AGNeil Gibson, PhD, OSI
PharmaceuticalsProfessor Sir Philip Cohen,
FRS, FRSE, Medical Research Council Protein Phosphorylation Unit, University of Dundee
Jeffrey Settleman, PhD, Department of Medicine, Harvard Medical School
References
Company Index with Web Addresses
Table of Contents
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Kinase Therapeutic Pipelines: An Assessment of Targets and Agents in Development
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CHI’s Second AnnualKinase Inhibitors: Moving Forward into Clinical StudiesOctober 21-22, 2008 – World Trade Center – Boston – Part of CHI’s Discovery On Target EventThis conference brings together the top players, experts, and deci-sion makers to inform about latest developments, opportunities, and challenges and to brainstorm and discuss in an interactive environ-ment the most pressing topics related to the task of moving kinase inhibitor–based drugs into clinical studies and beyond.Conference Session Topics:• Lead Optimization • Resistance and Safety • New Therapeutic Scopes For more information and to register, visit DiscoveryonTarget.com
GPCRs: Dawn of a New Era?Despite their popularity as drug targets, one can easily argue that the pharmacologic potential of G protein-coupled receptors (GPCRs) is far from exhausted. This report explores current and likely consequences of recent advances concerning GPCR x-ray structures, allosteric interactions, multimerization, and functional selectivity; ex-tensively tabulates marketed drugs and compounds in development (arranged by receptor type and subtype); presents in-depth interviews with recognized experts in the field.This report also spotlights numerous small pharmaceutical compa-nies, which tend to push the limits of GPCR pharmacology by attack-ing more targets and by attempting to apply cutting-edge concepts derived from basic research.For TOC and executive summary, visit InsightPharmaReports.com
CHI Insight Pharma Reports are written by experts who collabo-rate with CHI to provide a series of reports that evaluate the salient trends in pharmaceutical technology, business, and therapy markets.
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