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Lead Generation Strategies and Technologies in Drug Development - Emerging Techniques Such as Antisense Technology Will Allow Innovators to Minimize Costs

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Lead Generation Strategies and Technologies in Drug Development - Emerging Techniques Such as Antisense Technology Will Allow Innovators to Minimize Costs Summary GBI Research has released its latest report, “Lead Generation Strategies and Technologies in Drug Development - Emerging Techniques Such as Antisense Technology Will Allow Innovators to Minimize Costs” that provides key data, information and analysis of the major trends and developments in the drug devleopment business. The report provides a comprehensive insight into key technological developments, new approaches in lead generation and various technologies developed to accelerate it.The report also provides key alliances and collaborations in the industry to minimize costs and maximize productivity. This report is built using data and information sourced from proprietary databases, primary and secondary research and in house analysis by GBI Research’s team of industry experts. Scope The scope of the report includes - - Key technological developments and new approaches including case studies. - Case studies of new technologies and their implementation by companies in drug development industry - Key drivers and restraints that have a significant impact on the market. - Competitive benchmarking of leading CROs, covering their offerings and recent deals in drug development Reasons to buy The report will enhance your decision making capability. It will allow you to - - Compare the key capabilities and models of major technology solution providers with your requirements and optimize your R&D costs - Develop market entry and market expansion strategies by identifying the key drivers and challenges in the global drug development market - Develop effective strategies to maximize the advantages through the understanding of drug development and business models.

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									        Lead Generation Strategies and Technologies in Drug
       Development - Emerging Techniques Such as Antisense
         Technology Will Allow Innovators to Minimize Costs
 Reference Code: GBIHC092MR                                                                                                      Publication Date: June 2011


                                   Decrease in Approval of NME and Increase in R&D Cost are the Major Drivers for Lead
                                   Generation Strategies and Technologies in Drug Discovery Process
                                   Over time, the FDA; the regulatory agency for the US pharmaceutical market, has adopted a
The NME approvals were             progressively stricter regime for drug approval, resulting in a significant decrease in the number of
53 in 1996 which declined          new molecular entities (NMEs) approved over the past decade.
to 15 in 2010
                                    Lead Generation Strategies and Technologies in Drug Discovery, Decline In NME
                                    Approvals By FDA, 1996-2010

                                                                  60




                                                                  50
                                        Number of NME Approvals




                                                                  40




                                                                  30




                                                                  20




                                                                  10




                                                                   0
                                                                       1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010


                                    Source: GBI Research, FDA Website




                                   The FDA has been continuously criticized for its overly strict standards surrounding drug approvals.
                                   Following the cases of Vioxx, Exubera (insulin human [rDNA origin]) as well as product recalls of
                                   “Made in China” drugs, the agency has been more cautious in analyzing the risks and benefits of
                                   drugs before approving them.
                                   In 1996 the number of NMEs approved was 53. This declined to just 17 in 2002. In 2008, the
                                   number of NMEs approved was 21, reflecting a better picture than in 2007 when only 16 drugs, the
                                   lowest number of the last 13 years, were approved.
                                   This reduction in NME approvals reflects the need to accelerate the lead generation process by
                                   which potential lead molecules reach trials. The faster the molecule enters trials, the faster the
                                   results of its efficacy can be seen and applied.




Lead Generation Strategies and Technologies in Drug                                                                          GBIHC092MR / Published JUN 2011
Development - Emerging Techniques Such as Antisense
Technology Will Allow Innovators to Minimize Costs                                                                                                         Page 1
                                                                                           © GBI Research. This is a licensed product and is not to be photocopied
                                   Using In Silico Technology to Conduct Lead Generation Studies Improves the Quality of
                                   Data and Speeds up the R&D Process
                                   The in silico method of drug discovery is preferred over traditional laboratory methods due to its
                                   ability to process large amounts of data in comparatively less time. This preference is also based
                                   on its low cost and the growing computational resources of in silico methods.
                                   With modern day drug discovery encompassing large quantities of compounds and reducing the
                                   time period needed to examine them, the assistance of computer technology is inevitable. Thus,
                                   the need for the storage, management and analysis of large quantities of compounds has given
                                   rise to CADD as a tool to accelerate the modern day drug discovery process. CADD utilizes
                                   computational chemistry to discover and enhance optimization of the study drugs and related
                                   biologically active molecules. The objective is to predict the binding strength of given molecules in
                                   relation to their target.
                                   Currently, CADD represents various computational methods and resources used to assist the drug
                                   design and discovery process. Some of the major developments in CADD features include digital
                                   repositories, design libraries, fold recognition and virtual screening.
                                   Digital repositories contain detailed information on drugs and other useful compounds which are
                                   useful for studying the capabilities of chemical reactions. Similarly, design libraries also, have the
                                   potential to generate molecular variants. It also allows for the selection and sampling of chemical
                                   compounds with diverse characteristics. Fold recognition is used for studying sequence structure
                                   homology between protein sequences and structures and are helpful for inferring binding sites and
                                   molecular functions. Finally, virtual screening, a computerized version of HTS allows the systematic
                                   evaluation of large chemical libraries to identify potential lead candidates that can be synthesized
                                   and tested.
                                   Major stages of drug discovery that can utilize CADD include hit identification using virtual
                                   screening, hit-to-lead optimization of affinity and selectivity and lead optimization of other
                                   pharmaceutical properties while maintaining affinity.
                                   Contract Research Organizations are Emerging as Strategic Partners to Improve R&D
                                   Efficiency by Reducing Time to Market and Costs
                                   Lead generation studies make use of systems or models such as in vitro, in vivo and in silico
                                   models in order to conduct preclinical research and development studies. Absorption, distribution,
                                   metabolism, excretion and toxicology (ADMET) studies are conducted initially to investigate and
                                   correlate the test compound‟s chemical properties in preclinical systems with those of humans.
                                   There are a considerable number of contract research organizations (CROs) providing a wide
                                   range of preclinical design and testing services. Some of the top CROs such as Covance and
                                   Cyprotex offer both customized and standardized lead generation services and models to their
                                   clients (pharmaceutical and biotechnology companies) and continue to grow with strategic
                                   acquisitions and partnerships. Furthermore, CROs from Asian countries, notably India and China,
                                   such as Jubilant Biosys, Advinus and Shanghai ChemPartner are also emerging with customized
                                   offerings on early phase drug discovery.




Lead Generation Strategies and Technologies in Drug                                                     GBIHC092MR / Published JUN 2011
Development - Emerging Techniques Such as Antisense
Technology Will Allow Innovators to Minimize Costs                                                                                    Page 2
                                                                      © GBI Research. This is a licensed product and is not to be photocopied
                                      Lead Generation Strategies and Technologies in Drug Discovery, Strategic Or Tactical
                                      Advantages In Early Stage Drug Development Outsourcing


                                                                              Availability of
                                                                              superior drug
                                                                                discovery
                                                                              technologies

Fig 2
  &
Fig 27                                                                    Advantages of                               Decreased
                                             Superior and
                                                                        Outsourcing in Early                          Time and
                                             faster Go/ No                                                           Cost in Drug
                                              Go Decision                 Stage of Drug
                                                                           Development                                Discovery




                                                                           Avoid Failures in
                                                                           The Costly Late
                                                                            Stage Clinical
                                                                            Development

                                      Source: GBI Research




                                     For biopharmaceutical companies, the early stages in the drug development process play a crucial
                                     role in discovering and bringing safe and effective new compounds to the market. Outsourcing at
                                     this stage helps biopharmaceutical companies to access global patient populations and conduct
                                     rigorous early phase clinical research with decreased costs and in less time




  Lead Generation Strategies and Technologies in Drug                                                   GBIHC092MR / Published JUN 2011
  Development - Emerging Techniques Such as Antisense
  Technology Will Allow Innovators to Minimize Costs                                                                                  Page 3
                                                                      © GBI Research. This is a licensed product and is not to be photocopied
                                   1         Table of Contents
                                   1   Table of Contents ........................................................................................................................ 4
                                       1.1    List of Tables..................................................................................................................... 6
                                       1.2    List of Figures ................................................................................................................... 7
                                   2   Introduction .................................................................................................................................. 9
                                       2.1    GBI Report Guidance ........................................................................................................ 9
                                   3   The Drug Discovery Process: Defining Lead Generation .......................................................... 10
                                       3.1    Process of Early Preclinical Drug Discovery ................................................................... 10
                                          3.1.1     Pre-Discovery .......................................................................................................... 10
                                          3.1.2     Target Identification ................................................................................................. 11
                                          3.1.3     Target Validation ..................................................................................................... 12
                                          3.1.4     Lead Identification ................................................................................................... 12
                                          3.1.5     Early Safety Tests ................................................................................................... 13
                                          3.1.6     Lead Optimization.................................................................................................... 13
                                          3.1.7     Preclinical Testing ................................................................................................... 14
                                       3.2    Hit to Lead - Identifying Possible Structure ..................................................................... 15
                                          3.2.1     Strategies Used In Generating Potential Lead from Identified Hits .......................... 15
                                       3.3    Role of Lead Generation in the Path of Drug Development ............................................ 18
                                   4   Lead Generation Strategies in the Pharmaceutical Industry ...................................................... 19
                                       4.1    Massive Decline in Sales - Dependence on Blockbuster Drugs...................................... 19
                                       4.2    Need to Accelerate Lead Generation Process ................................................................ 20
                                          4.2.1     Stricter FDA Rules and Regulations for Drug Approval ........................................... 20
                                          4.2.2     Penetration of Aggressive Generic Companies ....................................................... 21
                                          4.2.3     The Economic Impact of Compound Attrition at Various Stages of Lead Discovery 23
                                          4.2.4     Drought in the R&D Pipeline Products (Low R&D Productivity) ............................... 25
                                       4.3    HTS Solutions for ADME Testing .................................................................................... 27
                                          4.3.1     In Vitro Studies of Drug Absorption ......................................................................... 27
                                          4.3.2     In Vitro Studies of Protein Binding ........................................................................... 29
                                       4.4    Fragment-Based Drug Discovery .................................................................................... 30
                                          4.4.1     Differences Between HTS and FBDD ...................................................................... 31
                                          4.4.2     Advantages of Fragment-Based Drug Design over High-Throughput Screening .... 31
                                          4.4.3     Applications of Mass Spectrometry in Fragment Library Screening ........................ 33
                                          4.4.4     Recent Advances in Structure-Based Fragment Docking and Virtual Screening..... 34
                                          4.4.5     Novel Strategy for the Design of a Fluorinated Fragment Library, Named LEF (Local
                                                    Environment of Fluorine) ......................................................................................... 35
                                          4.4.6     Ligand-Based Approach to In Silico Pharmacology ................................................. 38
                                       4.5    Antisense Technology as a Strategy ............................................................................... 38
                                          4.5.1     Isis Pharmaceuticals................................................................................................ 38
                                          4.5.2     CytRx Laboratories .................................................................................................. 38
                                       4.6    Iterative Focused Screening as a Strategy ..................................................................... 39
                                          4.6.1     Merck Frosst Canada .............................................................................................. 39
                                   5   Emerging Technology in Lead Generation ................................................................................ 40
                                       5.1    Improving High Throughput Screening ........................................................................... 40
                                          5.1.1     Overview ................................................................................................................. 40
                                          5.1.2     Case Study .............................................................................................................. 40
                                          5.1.3     Improving In Vitro Assays for HTS........................................................................... 41
                                          5.1.4     Whole Animal Imaging and Microscopy ................................................................... 41
                                       5.2    The Parallel Synthesis Approach .................................................................................... 42
                                          5.2.1     In Vitro Methods ...................................................................................................... 42
                                          5.2.2     In Silico Methods - Structure-Toxicity Relationships ................................................ 42
                                       5.3    Computerized Combinatorial Chemistry and 3D Molecular Modeling ............................. 43
                                          5.3.1     Overview ................................................................................................................. 43
                                          5.3.2     Service Providers .................................................................................................... 44
                                          5.3.3     Case Studies ........................................................................................................... 45


Lead Generation Strategies and Technologies in Drug                                                                                   GBIHC092MR / Published JUN 2011
Development - Emerging Techniques Such as Antisense
Technology Will Allow Innovators to Minimize Costs                                                                                                                            Page 4
                                                                                      © GBI Research. This is a licensed product and is not to be photocopied
                                     5.4    Molecular Bioimaging ...................................................................................................... 46
                                        5.4.1    Overview ................................................................................................................. 46
                                        5.4.2    Service Providers .................................................................................................... 46
                                        5.4.3    Case Study .............................................................................................................. 46
                                     5.5    Omics-Technology and Bioinformatics ............................................................................ 47
                                        5.5.1    Overview ................................................................................................................. 47
                                        5.5.2    Service Providers .................................................................................................... 47
                                        5.5.3    Case Study .............................................................................................................. 48
                                   6 Lead Generation Now and in the Future .................................................................................... 50
                                     6.1    R&D Models: Influence on Lead Generation ................................................................... 50
                                        6.1.1    Recent Technology Developments .......................................................................... 50
                                     6.2    A Novel Technology to Enhance Fragment-Based Drug Discovery ................................ 53
                                        6.2.1    ZoBio’s Target Immobilized NMR Spectroscopy Method for Fragment-Based Drugs
                                                  ................................................................................................................................ 53
                                   7 Pharmaceutical Outsourcing as a Strategy to Accelerate Lead Generation .............................. 55
                                     7.1    Early Stage Drug Development Outsourcing .................................................................. 55
                                        7.1.1    Strategic or Tactical Advantages of Outsourcing ..................................................... 55
                                        7.1.2    Case Study .............................................................................................................. 56
                                     7.2    Emerging Regions in the Global Contract Research Outsourcing Market for Early Stage
                                            Drug Development .......................................................................................................... 57
                                        7.2.1    Latin America........................................................................................................... 57
                                        7.2.2    Central and Eastern Europe (CEE) ......................................................................... 58
                                        7.2.3    India......................................................................................................................... 59
                                        7.2.4    China ....................................................................................................................... 61
                                   8 Major Contract Research Organizations in Drug Discovery ...................................................... 63
                                     8.1    Cyprotex Discovery Ltd. .................................................................................................. 63
                                        8.1.1    Business Overview .................................................................................................. 63
                                        8.1.2    Services ................................................................................................................... 63
                                     8.2    Shanghai ChemPartner .................................................................................................. 64
                                        8.2.1    Business Overview .................................................................................................. 64
                                        8.2.2    Services ................................................................................................................... 64
                                     8.3    Covance, Inc. .................................................................................................................. 65
                                        8.3.1    Business Overview .................................................................................................. 65
                                        8.3.2    Services ................................................................................................................... 65
                                     8.4    Caliper Life Sciences ...................................................................................................... 66
                                        8.4.1    Business Overview .................................................................................................. 66
                                        8.4.2    Services ................................................................................................................... 66
                                     8.5    GVK BIO ......................................................................................................................... 67
                                        8.5.1    Business Overview .................................................................................................. 67
                                        8.5.2    Services ................................................................................................................... 67
                                     8.6    Jubilant Biosys ................................................................................................................ 68
                                        8.6.1    Business Overview .................................................................................................. 68
                                        8.6.2    Services ................................................................................................................... 68
                                     8.7    Advinus Therapeutics ..................................................................................................... 69
                                        8.7.1    Business Overview .................................................................................................. 69
                                        8.7.2    Services ................................................................................................................... 69
                                     8.8    ITR Canada..................................................................................................................... 70
                                        8.8.1    Business Overview .................................................................................................. 70
                                        8.8.2    Services ................................................................................................................... 70
                                     8.9    MD Biosciences .............................................................................................................. 71
                                        8.9.1    Business Overview .................................................................................................. 71
                                        8.9.2    Services ................................................................................................................... 71
                                     8.10 PPD, Inc. ......................................................................................................................... 72
                                        8.10.1 Business Overview .................................................................................................. 72
                                        8.10.2 Services ................................................................................................................... 72


Lead Generation Strategies and Technologies in Drug                                                                                 GBIHC092MR / Published JUN 2011
Development - Emerging Techniques Such as Antisense
Technology Will Allow Innovators to Minimize Costs                                                                                                                         Page 5
                                                                                      © GBI Research. This is a licensed product and is not to be photocopied
                                     8.11 Ricerca Biosciences, LLC ............................................................................................... 73
                                        8.11.1 Business Overview .................................................................................................. 73
                                        8.11.2 Services ................................................................................................................... 73
                                     8.12 MPI Research ................................................................................................................. 74
                                        8.12.1 Business Overview .................................................................................................. 74
                                        8.12.2 Services ................................................................................................................... 74
                                   9 Lead Generation Strategies and Technologies in Drug Discovery - Appendix .......................... 75
                                     9.1    Market Definitions ........................................................................................................... 75
                                     9.2    Abbreviations .................................................................................................................. 75
                                     9.3    Research Methodology ................................................................................................... 76
                                        9.3.1    Coverage ................................................................................................................. 76
                                        9.3.2    Secondary Research ............................................................................................... 76
                                        9.3.3    Primary Research .................................................................................................... 76
                                        9.3.4    Expert Panel Validation ........................................................................................... 77
                                     9.4    Contact Us ...................................................................................................................... 77
                                     9.5    Disclaimer ....................................................................................................................... 77
                                     9.6    Sources ........................................................................................................................... 77


                                   1.1       List of Tables
                                   Table 1: Lead Generation Strategies and Technologies in Drug Discovery, Top 20 Patent
                                             Expirations During 2010-2014, Based on US Sales in Dollars ....................................... 19
                                   Table 2: Lead Generation Strategies and Technologies in Drug Discovery, Comparison of
                                             Microdialysis with Ultrafilteration .................................................................................... 29
                                   Table 3: Lead Generation Strategies and Technologies in Drug Discovery, Recent Success
                                             Stories in Virtual Screening ............................................................................................ 35
                                   Table 4: Lead Generation Strategies and Technologies in Drug Discovery, Application of SPR by
                                             Noxxon Pharmaceutical ................................................................................................. 37




Lead Generation Strategies and Technologies in Drug                                                                               GBIHC092MR / Published JUN 2011
Development - Emerging Techniques Such as Antisense
Technology Will Allow Innovators to Minimize Costs                                                                                                                      Page 6
                                                                                     © GBI Research. This is a licensed product and is not to be photocopied
                                   1.2       List of Figures
                                   Figure 1: Lead Generation Strategies and Technologies in Drug Discovery, Life Cycle of a New
                                              Drug ............................................................................................................................... 10
                                   Figure 2: Lead Generation Strategies and Technologies in Drug Discovery, Drug Discovery
                                              Process .......................................................................................................................... 11
                                   Figure 3: Lead Generation Strategies and Technologies in Drug Discovery, Applications of Lead
                                              Generation Process ....................................................................................................... 12
                                   Figure 4: Lead Generation Strategies and Technologies in Drug Discovery, Pathways For
                                              Optimizing Lead Through Screening .............................................................................. 13
                                   Figure 5: Lead Generation Strategies and Technologies in Drug Discovery, Effective Lead
                                              Optimization ................................................................................................................... 14
                                   Figure 6: Lead Generation Strategies and Technologies in Drug Discovery, Hit Evolution Form
                                              Drug-Like Hit .................................................................................................................. 16
                                   Figure 7: Lead Generation Strategies and Technologies in Drug Discovery, Isosteric Replacement
                                              Form Drug-Like Hit ......................................................................................................... 16
                                   Figure 8: Lead Generation Strategies and Technologies in Drug Discovery, Hit-Fragmentation In
                                              Lead Generation ............................................................................................................ 17
                                   Figure 9: Lead Generation Strategies and Technologies in Drug Discovery, Target Preference In
                                              Drug Discovery............................................................................................................... 18
                                   Figure 10: Lead Generation Strategies and Technologies in Drug Discovery, Decline In                                                    NME
                                              Approvals By The FDA, 1996-2010................................................................................ 20
                                   Figure 11: Lead Generation Strategies and Technologies in Drug Discovery, Original Abbreviated
                                              New Drug Application (ANDA) Approvals During 2001-2009 ......................................... 21
                                   Figure 12: Lead Generation Strategies and Technologies in Drug Discovery, Decision Check
                                              Points At Various Stages In Lead Generation ................................................................ 23
                                   Figure 13: Lead Generation Strategies and Technologies in Drug Discovery, Pharmaceutical and
                                              Biotech R&D Expenditure ($bn) versus Number of NME/BLA Approvals, the US, 1995-
                                              2009 ......................
								
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