Pipeline and Commercial Insight: Nicotine Dependence - Chantix issues overshadow vaccine potential

CHAPTER 1 EXECUTIVE SUMMARY 3
Scope of the analysis 3
Datamonitor insight into the nicotine dependence market 4
Key metrics 6
Related reports 6

CHAPTER 2 PATIENT POTENTIAL 8
Definition of nicotine dependence 9
The DSM-IV provides the most widely used definition of nicotine dependence 9
Diagnostic assessment tool characterizes level of dependence 10
Prevalence of tobacco smoking 11
Global number of smokers is expected to rise to 1.7 billion by 2025 11
Male smokers far outnumber their female counterparts in both developed and developing nations 12
Approximately 150 million people in the seven major markets are estimated to be current tobacco smokers 13
Prevalence of smoking in the US and UK has decreased steadily over the past decade 15
Smoking is less stigmatized in Germany and as a result rates have not fallen to the same extent as in the US and UK 18
Japanese men account for the highest seven major market smoking rate as antismoking legislations remain only loosely imposed 19
Smoking rates in developing nations are generally much higher than in developed countries 20
Significant smoking populations in BRIC nations represent substantial future market opportunity 20
GlaxoSmithKline targets multiple nicotine replacement therapy launches in emerging markets 21
Brazil - inspiring the world to quit smoking with shocking visual messages 21
Russia - female smoking rate rises but the government is now taking steps to combat smoking culture 22
India - smoking ban finally imposed in 2008 in a critical move to get the nation's estimated 120 million smokers to quit 23
China - accounts for almost one third of the world's entire smoking population 24
Global tobacco epidemic accounts for 5.4 million deaths annually 25
The World Health Organization's MPOWER policies are critical to helping reduce future tobacco-related illness and deaths in developing nations 26
The World Health Organization Framework Convention on Tobacco Control developed to counter the global tobacco epidemic 27
Epidemiology of nicotine dependence 27
Use of different criteria and methodologies limits study consistency 27
Risk factors for nicotine dependence 29
Genetic factors - susceptibility genes could lead to more tailored treatment 29
Psychiatric disorders increase likelihood of nicotine dependence and low quit rate success 30
Patient dynamics 31
Quit rate success is low with few individuals seeking help from their primary care physician or local services 31
UK quit rate dynamics - nicotine replacement therapies are used by the majority but National Health Service Stop Smoking Services rarely are 32
US quit rate dynamics - quit success rate stalls with more dependent smokers now remaining 34
French quit rate dynamics - historically, physicians have rarely motivated smokers to quit 35
Unmet needs in nicotine dependence 36
Reduction in relapse rate remains the primary clinical unmet need 37
Focusing on relapse prevention would be consistent with the chronic nature of nicotine dependence 37
Counseling platforms are essential to break the psychological dependence 38
Treatment duration is often too short for some patients 38
Chantix has demonstrated continuous abstinence through 24 weeks of treatment 39
Extended use of bupropion has been shown to delay relapse after smoking cessation 40
Need to increase presentation rates 41
Too few smokers accept that they would benefit from visiting a clinician in order to aid quitting 41
Lack of reimbursement and/or high cost of products is often a deterrent to quitting smoking 42
Medicaid coverage of recommended smoking cessation treatments has improved but is still not broad enough in many US states 42
Smoking cessation aids are sparsely covered by health insurance in Germany 44
Safety of smoking cessation therapies 44
Further research is required in specific patient populations for all smoking cessation therapies 44
Nicotine replacement therapies pose little risk to patients with cardiovascular diseases 45
Safety profiles of varenicline and bupropion have hindered their uptake 45
Nicotine replacement therapy options are still not broad enough 46
Products suffer from much slower onset of action compared to cigarettes 46
Rapid-acting gum or an improved nasal spray would be well-received by prescribers 47

CHAPTER 3 MARKET OVERVIEW 49
Market definition for this report 50
Treatment of nicotine dependence 50
Behavioral therapy 50
Telephone counseling - free expert advice anytime, anywhere 51
Internet-based programs - free information and extensive resources 51
Individual or group counseling programs - participants can share tips and advice 51
Nicotine replacement therapies 51
Nicotine patch (NicoDerm CQ, Nicorette, Habitrol/Nicotinell, Nicopatch) 52
Nicotine gum (Nicorette, NiQuitin, Nicotinell, Nicogum) 53
Nicotine lozenge (NiQuitin, Nicotinell, Nicopass) 53
Nicotine nasal spray and inhaler (Nicotrol/ Nicorette) 53
Approved non-nicotine containing medications 54
Bupropion (Zyban, Wellbutrin) 54
Varenicline (Chantix, Pfizer) 55
Clinical practice treatment guidelines 56
US Department of Health and Human Services 56
Ten key guideline recommendations call on all healthcare disciplines to work together 56
National Institute for Health and Clinical Excellence (NICE) published guidance 57
Recommendations aim to reduce health inequalities across social groups 57
Current market assessment 58
Prescription market sales dynamics 58
Rapid expansion of the prescription nicotine dependence market halts as market stabilizes out at $1.35 billion in 2008 58
The US remains the largest prescription nicotine dependence market despite a decline in 2008 61
Over-the-counter market sales dynamics 62
Over-the-counter nicotine dependence market value exceeds that of the prescription-derived market 62
Japanese and German over-the-counter nicotine dependence markets far exceed the prescription markets in each country 63
Future market assessment 64
The nicotine dependence market is forecast to grow strongly from 2009 to total over $3.82 billion in 2018 64
Three distinct phases will determine the prescription nicotine dependence market dynamics over the next 10 years 65
Key events in the forecast period - launch of two nicotine vaccines 66
Chantix (varenicline, Pfizer) - key marketed brand overview 66
Drug overview 66
Novel smoking cessation therapy launched in the US and UK during 2006 66
Combination of agonist and antagonist effects in smoking cessation 67
The UK's National Institute for Health and Clinical Excellence was quick to recognize Chantix's cost-effectiveness 68
'GETQUIT Support Plan' aims to improve compliance 69
Additional studies resulted in Japanese approval 69
Brand dynamics 70
Pfizer updates Chantix label to warn of risk for increased suicidal ideation 70
US sales negatively impacted by January 2008 label update 71
Tortoise and hare direct-to-consumer advertising campaign relaunched in September 2008 72
Expert opinion 72
Opinion leaders remain unanimously positive over Chantix's safety profile 72
Improved follow-up will be essential to re-establish brand confidence 74
Post-marketing studies in a range of patient subgroups will help to establish the truth behind the safety warnings 75
Real-world data analysis shows effectiveness of Chantix when combined with behavioral counseling 76
Forecasts to 2018 77
Base seven major market forecast - Chantix sales rebound in coming years 77
Scenario forecast in the US - Safety fears continue to hamper Chantix sales 79
Drug assessment 81
Chantix remains the most attractive approved nicotine dependence therapy 81
Clinical trial data - studies showed 44% of Chantix users remained abstinent during weeks 9-12 of treatment 82
Large Phase II study showed impressive continuous abstinence rates through 12 weeks 83
Phase III comparative trials demonstrated superior efficacy of Chantix versus bupropion and placebo 83
Post-treatment follow-up exhibited long-term abstinence of Chantix-treated patients 84

CHAPTER 4 PIPELINE OVERVIEW AND R&D DYNAMICS 85
Pipeline overview 86
Few companies appear willing to seize the opportunity in the vast nicotine dependence market 86
Vaccine products remain a key focus in the nicotine dependence pipeline 87
Four nicotine vaccines are now in clinical trials to treat nicotine dependence 87
A vaccine for the treatment of nicotine dependence would present many commercial advantages over current approaches 89
Nicotine vaccines have the potential for prophylactic use 90
Relapse prevention as a conceivable target indication for pipeline agents 91
Greatest promise for a nicotine vaccine may not be in smoking cessation but as a relapse-prevention tool 92
Market potential for a relapse prevention therapy will depend on patient perception 93
Discontinued or on-hold projects 95
Sanofi-Aventis - three late-stage development discontinuations scupper plans to expand into nicotine dependence market 95
Dianicline - project terminated as not adequately differentiated from Chantix 95
Surinabant - development discontinuation announced in October 2008 96
Rimonabant - FDA non-approvable letter for smoking cessation in February 2006 96
Nalmefene (Somaxon) - development program 'on hold' following unsuccessful Phase II/III study in pathological gambling 97
Positive Phase II results for the opioid antagonist in smoking cessation 97
Clinical trial design in nicotine dependence 98
Recommended measures to assess efficacy 98
Primary endpoint should measure abstinence out to at least 1 year after drug treatment 98
Secondary endpoints should include shorter abstinence measures and place an importance on assessments of withdrawal symptoms 99
Patient populations 100
Inclusion criteria require participants to smoke 10 or more cigarettes per day 100
Opinion leaders recommend inclusion of more heterogeneous participant samples 100
Relapse prevention study designs 101
Clinical trials incorporate two phases and a long-term follow-up to assess continued abstinence 101

CHAPTER 5 LATE-STAGE DRUG ANALYSIS AND FORECASTS 103
Key late-stage pipeline summary 104
Comparative forecasts 104
Comparative drug assessment 104
NicVAX (Nabi Biopharmaceuticals) 105
Drug overview 105
Fast Track status and agreed Special Protocol Assessment yet development partner remains elusive 105
Forecasts to 2017 106
NicVAX forecast to become the first vaccine approved for nicotine dependence 106
Development partner is essential for NicVAX to realize its market potential 107
Datamonitor drug assessment summary 108
Clinical positioning makes NicVAX an attractive licensing proposition 108
Marketing factors 109
Commercialization partner imperative for Nabi to compete effectively with Novartis and Cytos 109
As the first nicotine vaccine NicVAX will generate strong interest among physicians, patients and the general public 110
Patient potential 110
Individual variability in immunological response is a limiting factor 110
Satisfaction of unmet needs 111
Therapeutic response comparable to Chantix despite no use of behavioral counseling 111
Although an injection, convenient dosing regimen will increase compliance 112
Long-term presence of antibodies should reduce relapse rate 112
Favorable side-effect profile anticipated as NicVAX does not work centrally 113
Clinical trial data 113
Positive Phase II immunogenicity study results show increased antibody response with a more regular dosing schedule 113
One-year Phase IIb proof-of-concept study provides foundations for larger Phase III program 114
NIC-002 (Novartis and Cytos Biotechnology) 116
Drug overview 116
Secure Novartis licensing agreement offsets trailing development status compared to NicVAX 116
Forecasts to 2017 117
NIC-002 launch expected to trail NicVAX by a year 117
Datamonitor drug assessment summary 119
Novartis's CNS and vaccine experience greatly improves NIC-002's commercial attractiveness 119
Marketing factors 119
Novartis's marketing and sales experience bodes well for the launch of NIC-002 119
Second-to-market vaccine for nicotine dependence 120
Patient potential 120
Varied immunological response will restrict patient potential 120
Satisfaction of unmet needs 121
Impressive continuous abstinence only shown in high antibody level responders 121
Convenient dosing regimen will increase compliance 121
Long-term irreversibility of NIC-002 will reduce relapse rate 122
Favorable side-effect profile shown with new formulation 122
Clinical trial data 122
New Phase II study designed to assess efficacy of high nicotine antibody titers 122
Dose, regimen and formulation optimization studies essential to produce the best possible product for late-stage trials 123
Positive Phase II study results obtained through reanalysis of high antibody level responders 124
Unforecasted pipeline drugs 125
TA-NIC (Celtic Pharma) 125
'Rapid' enrollment completed in Phase IIb smoking cessation trial of TA-NIC 125
Celtic plans to outlicense TA-NIC after Phase IIb trial 126
GW-468816 (GlaxoSmithKline) 126
Product initially entered Phase II trials for smoking cessation over 5 years ago 126
Preclinical studies suggest NMDA receptor antagonists may have a potential role in nicotine dependence 127
Ongoing Phase II study assesses prevention of relapse in recently quit female smokers 127
EVT-302 (Evotec) 128
Exploratory Phase II craving study results announced in September 2008 129
Proof-of-concept Phase II quit-rate study initiated in September 2008 129
Studies of selegiline support hypothesis for using monoamine oxidase B inhibitors as smoking cessation therapy 130
Niccine (Independent Pharmaceutica AB) 130
Intramuscular vaccine primarily targeting the prevention of smoking relapse 130
Nicotine carrier protein selected to maximize the selectivity of the generated antibodies 131
Enrollment completed in relapse-prevention Phase II Scandinavian trial 131
ARD1600 (Aradigm) 132
Inhaled nicotine product to address acute craving for cigarettes 132
Phase I data show rapid achievement of comparative blood nicotine levels 132
Nicotine MDTS (Acrux) 133
Transdermal spray formulation of nicotine designed to combat the irritation often experienced with patches 133
QuitPak/INT003 (Cary Pharmaceuticals and IntelGenx) 133
Combination of mecamylamine and bupropion to work in synergy for overall smoking cessation goal 134
Phase I pharmacokinetic study shows sustained-release QuitPak is suitable for once-daily dosing 134

BIBLIOGRAPHY 135
Journal papers, books, and conference abstracts 135
Websites 138
Datamonitor reports 147

APPENDIX A 148
Data definitions, limitations and assumptions 148
Standard units 148
Japanese market data 148
Estimated 2008 sales revenue 148
Derivation of sales forecasts and pricing trends 148
Methodology 149
Indication-specific sales calculations 149
Forecast "sanity checking" - parallel patient population dynamics assessment 150

APPENDIX B 155
Contributing experts 155
About Datamonitor 156
About Datamonitor Healthcare 156
About the Disease analysis team 157
Disclaimer 158

List of Tables
Table 1: DSM-IV criteria for nicotine dependence 9
Table 2: Fagerström Test for Nicotine Dependence 11
Table 3: Adult prevalence of tobacco smoking (%) across the seven major markets as reported by the World Health Organization, 2008 14
Table 4: Current tobacco smoking prevalence in the seven major markets, 2008 15
Table 5: Adult prevalence of tobacco smoking (%) in Brazil, Russia, India and China, 2001-06 21
Table 6: Results of epidemiology studies of nicotine dependence across the seven major markets 28
Table 7: Key nicotine replacement therapies, 2008 52
Table 8: Prescription sales and growth dynamics of the key nicotine dependence products in the seven major markets, 2004-07 60
Table 9: Datamonitor's estimated launch dates for prescription nicotine dependence products across the US, 5EU and Japan, 2009-2018 66
Table 10: Chantix: key facts, 2009 67