Drug Repositioning Strategies - Serendipity by design

Introduction
Drug repositioning has several advantages over traditional discovery-reduced cost, risk and time to market-compared with traditional discovery, providing an attractive prospect for Big Pharma, scrambling to fill pipelines in an increasingly harsh market environment. As competition to inlicense candidates drives the price of this strategy up, repositioning presents a cost effective alternative.

Report Highlights
Highlights
Despite increasing R&D investment, productivity has been declining, at a time when Big Pharma is contending with late–stage pipeline failures and more rigorous drug approval procedures, in addition to external challenges in the form of generic competition and pricing pressures.

The cost savings, accelerated path to market, and lower risks that repositioning brings relative to traditional discovery are attractive to Big Pharma, which has thus far been filling pipeline gaps by in–licensing, a practice which has become more expensive as competition for candidates increases.

The companies involved in repositioning currently differ greatly in the methodologies used, in addition to their disease focus, however as the strategy gains traction, the industry is likely to undergo considerable consolidation.
[Studien Infos ausblenden]

TABLE OF CONTENTS
CHAPTER 1 EXECUTIVE SUMMARY 4
Scope of the report 4
Key findings 4
CHAPTER 2 OVERVIEW OF DRUG REPOSITIONING 8
Drug repositioning as a phenomenon distinct from lifecycle management 8
The basis of repositioning 8
The motives for repositioning 9
Increased R&D investment has had little impact on productivity 10
Greater hurdles to obtaining drug approval 11
Late-stage failures 12
Drug repositioning as a means of reducing risk, cost and time-to-market 13
Conventional de novo drug development 14
The development of a repositioned drug is accelerated relative to a conventional candidate 15
A growing trend toward systematic rather than serendipitous repositioning 16
Viagra (sildenafil) - from angina to impotence in one serendipitous leap 17
Duloxetine's dual role established through informed insight 17
The success of sildenafil and duloxetine was facilitated by the prevailing market environment 17
Informed insight could lead to diabetes drug for epilepsy 18
Thalidomide represents an unusual form of drug repositioning 18
Repositioning technologies 19
The resistors to repositioning 20
Most repositioned drugs are old, with little patent protection 21
Repositioned drugs tend to be protected by method of use patents 21
Seeking drug approval for marketed drugs 22
Prior safety and toxicology data may be incomplete or inadequate 23
Repositioning a drug for which primary indication use is still active 23
Acquiring discontinued drugs 24
CHAPTER 3 KEY PLAYERS IN DRUG REPOSITIONING 25
Ore Pharmaceuticals - one of the most established players in drug repositioning 26
Ore Pharmaceuticals's corporate history 26
Ore Pharmaceuticals's screening process is a composite of several technology platforms 28
In vivo spatial mapping of drug action and biomarker changes 29
Cellular and molecular characterization of drug action 29
In silico approach further validates link between drug and disease 29
Successful candidates returned to innovator 30
Celentyx - a new player on the repositioning block 31
Novel immune functions for old drugs 31
Celentyx uses cell-based assays to find new indications 33
CombinatoRx - combines old drugs for new indications 33
High-throughput combinatorial methodology 34
CombinatoRx's early-stage pipeline 35
CRx-102 ready for Phase III development 35
CombinatoRx receives method of use patent for psoriasis drug 36
Melior - systemizing serendipity 38
High-throughput in vivo drug screening 38
Melior has three early-stage pipeline drugs 39
Melior has formed collaborations with several Big Pharma players 40
Sosei - a pioneer drug repositioning company 40
Sosei's corporate history 40
Sosei grows its pipeline through partnership 41
KineMed - pathways to repositioning 43
KineMed's proprietary technology to assess drug-induced signal transduction flux 44
Pipeline growth through collaboration 44
Dynogen - a company with a narrow therapeutic focus 45
Pipeline of drugs with a gastrointestinal or genitourinary focus 45
Dynogen's partnerships and collaborations 47
Other repositioning companies 47
Synosia 47
DanioLabs 48
Pharnext 48
Arachnova 49
CHAPTER 4 DRUG REPOSITIONING CASE STUDIES 50
Drugs repositioned through serendipity 50
Mozobil (plerixafor) - the repositioning of a discontinued drug 50
Stem cell mobilization for cancer patients 52
Blind screen throws up antibiotics to treat neurological disease 53
Ceftriaxone as the most potent neuroprotector 53
Raloxifene - a marriage of serendipity and informed insight 54
One drug, two mechanisms of action 55
Drugs repositioned through informed insight 56
Rituximab - rational repositioning for multiple indications 57
Approval for rheumatoid arthritis 57
Off-label use for systemic lupus erythematosus but failure in clinical trials 58
In development for multiple sclerosis 59
The risks of repositioning 59
HIV protease inhibitor to treat cancer 60
Viracept (nelfinavir) most promising of the protease inhibitors 60
Maraviroc 62
Etanercept - from inflammation to neurodegeneration 63
Repositioning which does not fall neatly into either class 64
Rapamycin, antifungal, immunosuppressant and cancer treatment 64
Antiangiogenic properties of rapamycin 65
Rapamycin analog Certican (everolimus) in development for cancer 66
Avastin - reverse repositioning 67
CHAPTER 5 REPOSITIONING GOING FORWARD 70
Prospect of internal repositioning by innovators 70
Relationship between innovators and repositioners 71
Acquisition of repositioning companies by innovators 71
Repositioning companies fueling their own development process 72
Competition to acquire drug candidates could lead to consolidation 72
One drug, too many indications? 73
Emerging approaches - public sector funded small molecule based screening sectors 73
Optimization of repositioning 74
Combinatorial development the way forward 74
CHAPTER 6 BIBLIOGRAPHY 76
Publications and online articles 76
Conference literature 86
Datamonitor resources 86
APPENDIX 88
Abbreviations 88
[Inhaltsverzeichnis ausblenden]

LIST OF TABLES
Table 1: Breakdown of R&D investment for US Pharma, 2005 16
Table 2: Ore Pharmaceuticals's alliance profile, 2005-07 30
Table 3: CombinatoRx's recent alliances, 2006-07 37
LIST OF FIGURES
Figure 1: Ways to reposition drugs 9
Figure 2: Weak pipelines drive adoption of drug repositioning 10
Figure 3: R&D investment and productivity out of synch, 1996-2006 11
Figure 4: Drug repositioning versus de novo drug development 13
Figure 5: The innovative drug development process 14
Figure 6: Drug repositioning as a means of streamlining the development process 15
Figure 7: Methods used to identify suitable drug candidates for repositioning 19
Figure 8: Major issues impacting on the repositioning process 20
Figure 9: Summary of some of the major companies involved in repositioning 25
Figure 10: Ore Pharmaceuticals's multidisciplinary drug technology platform 28
Figure 11: Outline of Celentyx's drug repositioning plan 32
Figure 12: CombinatoRx's drug development pipeline, 2008 35
Figure 13: Melior's drug development pipeline, 2008 39
Figure 14: Sosei's drug development pipeline, 2008 42
Figure 15: KineMed's metabolic pathway plan, 2008 43
Figure 16: Dynogen's drug development pipeline, 2008 46
Figure 17: Plerixafor's action in HIV and stem cell mobilization 51
Figure 18: Antibiotic and neuroprotective actions of ceftriaxone 54
Figure 19: Raloxifene's action in osteoporosis and breast cancer 55
Figure 20: Rituximab approved and/in development for several indications 57
Figure 21: Protease inhibitor nelfinavir in cancer 60
Figure 22: Maraviroc in HIV and rheumatoid arthritis 62
Figure 23: Etanercept in Alzheimer's disease 64
Figure 24: Rapamycin pathways in cancer and immunosuppression 65
Figure 25: Avastin versus Lucentis for age-related macular degeneration 67
Figure 26: Issues impacting drug repositioning in the future 70
[Tabellenverzeichnis ausblenden]