Pipeline and Commercial Insight: Migraine - Challenges ahead for first-in-class developments

Introduction

After 4 years of steady growth, the migraine market across the seven major regions was valued at $4.6 billion in 2008. However, following US patent expiries of both the acute migraine market leading brand, Imitrex (sumatriptan; GlaxoSmithKline), and leading prophylactic Topamax (topiramate; Johnson & Johnson), the market value plummeted by almost $1.5 billion from 2008 to $3.6 billion in 2009.

Scope

*Analysis of current migraine treatment approaches and drug recommendations, patient acquisition process and unmet medical needs.

*In depth analysis of historic (200509) and future (20102019) seven major market prescription sales dynamics.

*Review of the migraine drug pipeline dynamics, including detailed profiling of key late-stage products.

*Commercial and clinical assessment of key late-stage pipeline drugs, with key opinion leader comment and region-specific sales forecasts to 2019.

Highlights

In 2019, the seven major migraine market total is forecast to reach $2.8 billion. While high generic competition will continue to dictate the US market decline, proposed or enacted price reductions in the European countries will offset the uptake of new products and inhibit growth in this region.

Sumavel DosePro (sumatriptan needleless injection; Zogenix and Astellas) and Levadex (dihydroergotamine mesylate orally inhaled; MAP Pharmaceuticals) have been designed to provide a rapid acting and convenient relief of migraine. However, high cost, associated reimbursement challenges and patient preference for oral pills will limit uptake of both.

Despite upcoming regulatory uncertainty and future reimbursement hurdles, Allergan's Botox is set to become the first product approved for chronic migraine. Separately, while recent safety issues represent a major knock-back for Merck & Co., telcagepant is still predicted to become a useful alternative to the triptans.

Reasons to Purchase

*Quantify the current and future size of the migraine market.

*Identify potential licensing opportunities based on product portfolios and anticipated market needs.

*Understand the country-specific impact of key events in the migraine market during the forecast period 2010 to 2019.

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Overview 1
Catalyst 1
Summary 1
About Datamonitor Healthcare 2
About the central nervous system pharmaceutical analysis team 2
Executive Summary 3
Strategic scoping and focus 3
Datamonitor insight into the migraine market 3
Related reports 5
Upcoming related reports 5
Table of Contents 6
1. Patient Potential 7
Key findings 7
Definition of migraine 8
Definition 8
Migraine is a chronic primary headache disorder 8
The five distinct stages of a migraine 8
Pathophysiology 8
Newer neurovascular theory assumes that a complex series of events initiates migraine 8
Etiology 9
Convincing genetic linkage to migraine susceptibility remains elusive 9
Gender ratio points to a possible genetic influence 9
Patient segmentation 10
The two major types of migraine account for the vast majority of cases 10
Migraine with aura affects approximately one in 10 migraineurs 10
Migraine without aura is the most common and also disabling subtype 11
Menstrual migraine affects between 50% and 60% of female migraineurs 11
Epidemiology 12
Migraine has an understated impact on population wellbeing 12
Seven major markets 12
About 10% of the general adult population are thought to suffer from migraine 12
Prevalence of migraine in adolescents is lower than in adults but represents an attractive indication expansion strategy 14
Rest of the world 15
Migraine prevalence appears to be similar across the globe but detailed studies are sparse 15
Migraine by treatment method: prophylactic and chronic migraine 16
Prophylactic treatment of migraine is vastly underutilized 16
Chronic migraine accounts for 1.4-2.2% of the general population but debate over the most accurate definition persists 16
Clinical unmet need in migraine 19
Unmet need one: sustained pain relief 19
Unmet need two: reduced headache relapse rates 20
Unmet need three: more efficacious prophylactic drugs 21
Unmet need four: safer and better tolerated drugs for both the acute and preventative treatment 22
Unmet need five: rapid onset of action 23
2. Market Overview 24
Key findings 24
Market definition for this report 25
Seven major market current and future market assessment 25
Future triptan genericization will see the migraine market value continue to decline through to 2019 25
Market volume to maintain consistent growth over forecast period 26
Further patent expiries and tough cost-control measures will inhibit 5EU market growth 27
Despite biannual price cuts Japan will represent the only growth market as demand for migraine prescriptions continues 29
Triptans to remain the leading class despite experiencing considerable sales decline 30
Rest of the world snapshot 32
The rest of the world migraine market accounted for 18% of the global value in 2009 32
Rest of the world region market value also contracted in 2009 32
Rest of the world accounts for half of the global migraine market volume 33
Non-narcotic analgesics are prescribed to a greater extent outside of the seven major markets 34
BRIC and MENA provide strongest historical 5-year growth 35
Patient acquisition process 36
Introduction 36
Patient care pathway 36
How to decide on acute treatment or prophylaxis 38
3. Brand Dynamics 40
Key findings 40
Overview of competitive landscape 41
The FDA approves two new acute migraine products in 2009 41
Reimbursement/tiering of brands 42
New products struggle to achieve favorable tiering in presence of generic sumatriptan and established triptan brands 42
Managed care actively limits the availability of the triptans 43
Leading brands suffer generic erosion following patent expiry 43
Imitrex (sumatriptan; GlaxoSmithKline) 44
Market-leading acute migraine brand's reign at the top comes to an end 44
A range of delivery method reformulations and additional indications offer patients a greater treatment choice 45
Topamax (topiramate; Johnson & Johnson) 46
Formal approval drives sales of market-leading migraine prophylactic 46
Once-daily medication effective at reducing the number of migraine headaches experienced 48
Treximet (sumatriptan + naproxen; GlaxoSmithKline/Pozen) 50
Drug overview 50
Drug profile 50
Product positioning 51
Franchise extension strategy falls short as launch date delayed 51
Post-marketing studies focus on probable migraine and short-acting triptan non-responders 51
SWOT analysis 51
Clinical and commercial attractiveness 52
Brand forecast to 2019 54
Tiering status and availability of generic sumatriptan to limit Treximet's market success 54
Sumavel DosePro (sumatriptan needleless injection; Zogenix/Astellas) 55
Drug overview 55
Drug profile 57
Product positioning 57
Rapid acting sumatriptan formulation in a simple to use, needle-free delivery system 57
SWOT analysis 58
Clinical and commercial attractiveness 59
Brand forecast to 2019 61
Niche patient population and direct competition from injectable subcutaneous sumatriptan will limit uptake 61
Cambia (diclofenac potassium for oral solution; Nautilus Neurosciences) 63
Drug overview 63
Drug profile 64
Product positioning 64
New diclofenac formulation provides well-tolerated fast onset of action 64
SWOT analysis 66
Clinical and commercial attractiveness 66
Brand forecast to 2019 68
Small sales force and high price point will limit returns for Cambia 68
4. Pipeline Overview and R&D Dynamics 71
Key findings 71
Pipeline overview 72
Pipeline consists of reformulations and novel mechanisms 72
Acute treatment remains the focus of migraine developers 73
A lack of Phase I and preclinical compounds suggest interest is low in migraine 74
A wide variety of delivery methods are present in the migraine pipeline 76
5. Pipeline Analysis and Forecasts: Acute Migraine Drugs 78
Key findings 78
Overview of acute migraine treatment pipeline 79
Comparative forecasts 80
Datamonitor pipeline assessment summary 81
Definition of current comparator therapy 81
Imitrex remains Datamonitor's acute migraine gold standard 81
Levadex (dihydroergotamine mesylate orally inhaled; MAP Pharmaceuticals) 82
Drug overview 82
Drug profile 83
Clinical trial data 83
MAP sets out final studies required for NDA submission 83
Phase III FREEDOM-301 trial meets all four primary efficacy endpoints 84
SWOT analysis 85
Clinical and commercial attractiveness 86
Satisfaction of unmet needs 88
Novel pharmacokinetic profile provides a rapid onset of action in a more convenient administration 88
New option for non-responders seeking alternative treatments 90
Forecasts to 2019 91
Levadex to become a useful alternative acute migraine medication 91
Telcagepant (MK-0974; Merck & Co) 93
Drug overview 93
Drug profile 93
Clinical trial data 94
Additional safety study deemed necessary to counter concerns that arose from exploratory migraine prevention study 94
Menstrual migraine prevention study: long-term safety evaluation through a new indication assessment 94
Extensive clinical program sees all Phase III studies meet primary efficacy endpoints 95
SWOT analysis 98
Clinical and commercial attractiveness 98
Satisfaction of unmet needs 100
Lack of vasoconstrictor effects and promising general tolerability profile offsets recent safety concerns 100
Forecasts to 2019 102
Telcagepant will generate significant sales as an important triptan alternative 102
Zelrix (sumatriptan transdermal patch; NuPathe) 104
Drug overview 104
Drug profile 105
Clinical trial data 105
Statistical significance achieved at all pre-defined 2-hour efficacy endpoints in pivotal Phase III study 105
Two open-label Phase III safety trials and two pharmacokinetic trials are ongoing 106
SWOT analysis 107
Clinical and commercial attractiveness 107
Satisfaction of unmet needs 109
Patch formulation provides useful new route of administration for migraine patients experiencing nausea 109
Forecasts to 2019 111
Additional sumatriptan formulation expected to struggle to gain market traction 111
Other drugs in development for the acute treatment of migraine 112
MT400-Low dose (naproxen & sumatriptan; Pozen) 112
Pozen exercises rights to develop low-dose Treximet formulation for ex-US territories 112
AZ-001 (Staccato prochlorperazine; Alexza Pharmaceuticals) 112
Development of orally inhaled candidate temporarily suspended as Alexza directs resources elsewhere 112
Phase IIb trial meets primary efficacy endpoint of 2-hour pain relief 113
BGG492 (Novartis) 114
Phase II clinical trial data awaiting for AMPA receptor antagonist 114
BI 44370 (Boehringer Ingelheim) 114
Boehringer Ingelheim re-enters the CGRP fold with a new oral candidate 114
Lasmiditan (COL-144; CoLucid Pharmaceuticals) 115
Selective 5HT1F agonist anticipated to deliver efficacy without vasoconstrictor activity 115
Dose-ranging Phase IIb study of oral lasmiditan meets primary efficacy endpoint 115
MTR-106 (Meditor Pharmaceuticals) 116
Proposed NOS inhibitor shows promise in small Phase II study 116
Nasal carbon dioxide (Capnia) 117
New Phase II study completed in 2009 for intranasal carbon dioxide candidate 117
NGX424 (tezampanel; Raptor Pharmaceuticals) 117
Injectable ionotropic glutamate receptor antagonist remains in Phase II as development partner is sought 117
NVD-201 (sumatriptan oral spray; Novadel Pharma) 118
Progress has been slow for novel oral spray sumatriptan formulation 118
NXN-188 (NeurAxon) 119
Dual-action selective nitric oxide synthase inhibitor and 5HT agonist offers promise in migraine with aura 119
Three active confirmative Phase II studies to evaluate NXN-188 administered as three 200mg capsules 119
ROX-828 (ketorolac; Roxro Pharma) 120
Intranasal formulation of emergency room NSAID on hold as Roxro focuses on launch of Spirix 120
Proof of concept Phase II study results merit further clinical investigation 120
Early-stage compounds in development for the acute treatment of migraine 121
6. Pipeline Analysis and Forecasts: Migraine Prophylaxis Drugs 122
Key findings 122
Overview of migraine prophylaxis treatment pipeline 123
Definition of current comparator therapy 123
Topamax is Datamonitor's migraine prophylaxis gold standard 123
Botox (onabotulinumtoxinA; Allergan) 124
Drug overview 124
Drug profile 125
Clinical trial data 125
PREEMPT clinical program forms basis of chronic migraine filing 125
PREEMPT 1 misses primary efficacy endpoint in reducing the frequency of headache episodes 126
PREEMPT 2 meets all primary and secondary headache symptom measures 129
SWOT analysis 130
Clinical and commercial attractiveness 131
Satisfaction of unmet needs 133
Seeking approval to treat the most underserved and debilitating migraine population 133
Difficulty predicting responders will provide a stiff clinical challenge 134
Forecasts to 2019 136
Botox will generate the majority of its sales in the US amid anticipated reimbursement challenges 136
Other drugs in development for the prophylactic treatment of migraine 139
E2007 (perampanel; Eisai) 139
AMPA receptor antagonist remains in Eisai's pipeline although no development announced since 2006 139
Horizant (GSK1838262/XP13512/gabapentin enacarbil; XenoPort/GlaxoSmithKline) 139
Phase II migraine study nears completion while the FDA rejects the drug for restless legs syndrome 139
Tonabersat (SB-220453; Minster Pharmaceuticals) 140
GAP junction blocker misses primary efficacy endpoint in Phase IIb TEMPUS study 140
Early-stage compounds in development for the prophylactic treatment of migraine 142
Bibliography 143
Journal articles and conference abstracts 143
Websites 147
APPENDIX 152
Forecasting assumptions 152
New product launches 152
Patent expiries 152
Methodology 153
Datamonitor forecast methodology 153
Definition of a standard unit 153
Exchange rates 153
Country group definitions 154
Rest of European Union 154
Middle East and North Africa (MENA) 154
Rest of World 154
Migraine-specific sales calculations 155
ATC classes included in 'others' to define the migraine market 155
Datamonitor drug assessment scorecard 155
Acute migraine pipeline drug assessment scorecard 156
Migraine prophylaxis pipeline drug assessment scorecard 156
Contributing experts 157
Conference attendance 158
About Datamonitor 159
About Datamonitor Healthcare 159
About the Disease analysis team 159
Datamonitor consulting 160
Disclaimer 162
List of Tables
Table 1: One-year prevalence of migraine in the seven major markets, 2010 13
Table 2: Prevalence of migraine in the adult population across the seven major markets (000s), 2010 14
Table 3: Triptan 24 hours sustained pain-freedom rate 20
Table 4: Regional migraine market sales value ($m) and sales volume (IMS standard units) dynamics across the seven major markets, 2004-2018 28
Table 5: Global sales ($m) dynamics of the migraine market, 2005-09 33
Table 6: Representative formulary tier status in the US for leading acute migraine brands, 2010 42
Table 7: Imitrex (sumatriptan) - drug profile, 2010 44
Table 8: Topamax (topiramate; Johnson & Johnson) - drug profile, 2010 47
Table 9: Treximet (sumatriptan 85mg + naproxen sodium 500mg) - drug profile, 2010 50
Table 10: Datamonitor's drug assessment scorecard for Treximet in migraine, 2010 54
Table 11: Sumavel DosePro (sumatriptan needleless injection; Zogenix/Astellas) - drug profile, 2010 57
Table 12: Datamonitor's drug assessment scorecard for Sumavel DosePro (sumatriptan needleless injection; Zogenix/Astellas) in migraine, 2010 61
Table 13: Migraine-specific sales forecast for Sumavel DosePro (sumatriptan needleless injection; Zogenix/Astellas) in the seven major markets ($m), 2010-2019 62
Table 14: Cambia (diclofenac potassium for oral solution) - drug profile, 2010 64
Table 15: Pivotal Phase III clinical efficacy results of Cambia in the acute treatment of migraine 65
Table 16: Datamonitor's drug assessment scorecard for Cambia (diclofenac potassium for oral solution; Nautilus Neurosciences) in migraine, 2010 68
Table 17: Migraine-specific sales forecast for Cambia (diclofenac potassium for oral solution; Nautilus Pharmaceuticals) in the seven major markets ($m), 2010-2019 70
Table 18: Products in mid- to late-stage clinical development (Phase II-approved) for migraine, 2010 72
Table 19: Products in Phase I and preclinical development for migraine, 2010 73
Table 20: Products in mid-to-late stage clinical development (Phase II-pending approval) for the acute treatment of migraine, 2010 79
Table 21: Levadex (dihydroergotamine mesylate orally inhaled) - drug profile, 2010 83
Table 22: Key clinical trial data points for Levadex (dihydroergotamine mesylate orally inhaled; MAP Pharmaceuticals) from the Phase III FREEDOM-301 acute migraine study, 2009 84
Table 23: Datamonitor's drug assessment scorecard for Levadex (dihydroergotamine mesylate orally inhaled; MAP Pharmaceuticals) in migraine, 2010 88
Table 24: Migraine-specific sales forecast for Levadex (dihydroergotamine mesylate orally inhaled; MAP Pharmaceuticals) in the seven major markets ($m), 2010-2019 92
Table 25: Telcagepant (MK-0974) - drug profile, 2010 93
Table 26: Key clinical trial data points for telcagepant (MK-0974; Merck & Co) in a placebo-controlled acute migraine study announced in September 2008 95
Table 27: Key clinical trial data points for telcagepant (MK-0974; Merck & Co) in a placebo-controlled comparative acute migraine study announced in June 2008 96
Table 28: Datamonitor's drug assessment scorecard for telcagepant (MK-0974; Merck & Co.) in migraine, 2010 100
Table 29: Migraine-specific sales forecast for telcagepant (MK-0974; Merck & Co.) in the seven major markets ($m), 2010-19 103
Table 30: Impacting factors on migraine-specific revenues of telcagepant, 2010-19 104
Table 31: Zelrix (sumatriptan transdermal patch) - drug profile, 2010 105
Table 32: Key clinical trial data points for Zelrix (sumatriptan transdermal patch; NuPathe) from the Phase III acute migraine study 106
Table 33: Datamonitor's drug assessment scorecard for Zelrix (sumatriptan transdermal patch; NuPathe) in migraine, 2010 109
Table 34: Migraine-specific sales forecast for Zelrix (sumatriptan transdermal patch; NuPathe) in the seven major markets ($m), 2010-2019 111
Table 35: Key clinical trial data points for AZ-001 (Staccato prochlorperazine; Alexza Pharmaceuticals) from the Phase IIb acute migraine study 113
Table 36: Ongoing NXN-188 (NeurAxon) Phase II migraine studies, 2010 120
Table 37: Products in Phase I and preclinical development for the acute treatment of migraine, 2010 121
Table 38: Products in mid-to-late stage clinical development (Phase II-approved) for the prophylactic treatment of migraine, 2010 123
Table 39: Botox (onabotulinumtoxinA; Allergan) - drug profile, 2010 125
Table 40: Efficacy of Botox (onabotulinumtoxinA; Allergan) following the 24-week double-blind phase of the PREEMPT 1 (Phase III Research Evaluating Migraine Prophylaxis Therapy) study 128
Table 41: Efficacy of Botox (onabotulinumtoxinA; Allergan) following the 24-week double-blind and 56-week open-label phases of the PREEMPT (Phase III Research Evaluating Migraine Prophylaxis Therap1 study 129
Table 42: Datamonitor's drug assessment scorecard for Botox (onabotulinumtoxinA; Allergan) in migraine, 2010 133
Table 43: Migraine-specific sales forecast for Botox (onabotulinumtoxinA; Allergan) in the seven major markets ($m), 2010-19 136
Table 44: Impacting factors on migraine-specific revenues of Botox (onabotulinumtoxinA; Allergan), 2010-19 138
Table 45: Products in Phase I and preclinical development for the prophylactic treatment of migraine, 2010 142
Table 46: Datamonitor's launch date estimation for migraine products in the US, 5EU and Japan, 2010-2019 152
Table 47: Patent expiry dates for key migraine brands in the seven major markets, 2010019 152
Table 48: Other ATC classes included for migraine market definition, 2008 155
Table 49: Datamonitor's drug assessment parameters for key late-stage acute migraine pipeline therapies 156
Table 50: Datamonitor's drug assessment parameters for key late-stage migraine prophylaxis pipeline therapies 157
List of Figures
Figure 41: Methodology for forecasting price to remove impact of currency fluctuations on future trend 154

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