Pipeline Insight: Epilepsy - Past successes hard to emulate in highly genericized market

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Pipeline Insight: Epilepsy - Past successes hard to emulate in highly
genericized market
Published on May 2010

Report Summary

Introduction

Sales of antiepileptic drugs totaled $3.5 billion in 2009 across the seven major markets (US, Japan, France, Germany, Italy, Spain
and the UK). Datamonitor anticipates the combination of continuing strong historical growth dynamics and the uptake of the late-stage
pipeline drugs to result in the market value peaking at $5.1 billion in 2017, after which a new wave of patent expiries hits the US.

Scope

*Analysis of current epilepsy treatments, unmet market needs and the impact of generics.

*Review of the late-stage epilepsy pipeline, including analysis of key R&D company strategies.

*In depth analysis of historic (20052009) and future (20102019) seven major market sales value dynamics.

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

Highlights

With more convenient dosing and a purported improved safety profile over Trileptal and Tegretol, Stedesa (eslicarbazepine,
Sepracor/Eisai) is forecast to become the best-selling pipeline antiepileptic drug. Factoring monotherapy approval and first-line use,
epilepsy-specific sales are forecast to top $400m across the seven major markets by 2019.

Rikelta (brivaracetam, UCB) is forecast to generate almost $375m by 2019. With to UCB's already extensive epilepsy portfolio,
Datamonitor expects careful positioning will negate significant sales cannibalization. Use will be chiefly among refractory patients with
partial seizures, with monotherapy approval important to commercial success.

Three products are in late-stage development for the at-home management of acute seizures, a market dominated by Diastat
(diazepam rectal gel, Valeant). With all seeking to provide an improved administration method, Ikano's intranasal midazolam (ITI-111)
is set to become the new market leader with approximately $30m in sales by 2019.

Reasons to Purchase

*Analyze competitive environment at time of product launch.

*Validate internal forecasts and market potential for pipeline products.

*Identify licensing opportunities based on company portfolio and market needs.

Pipeline Insight: Epilepsy - Past successes hard to emulate in highly genericized market Page 1/11


Table of Content

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 epilepsy market 3
Related reports 5
Upcoming related reports 5
Table of Contents 6
1. Pipeline Overview and Dynamics 7
Key findings 7
Pipeline overview 8
Epilepsy pipeline shows moderate innovation 8
Classification of pipeline products 9
GABA enhancers and ion channel modulators account for two-thirds of the late-stage epilepsy pipeline 9
Investigated epilepsy types for each key pipeline drug 10
Adjunctive therapy for refractory partial seizures is typically the initial indication 10
Comparative forecasts 11
Pipeline compounds from traditional classes to boost market sales 11
Late-stage compounds in development set to achieve significant market share 12
Datamonitor's pipeline assessment summary 14
Keppra remains the drug to beat, even 10 years after initial approval 14
Key companies involved in the epilepsy pipeline 14
UCB 15
A novel mode of action and specific focus on epilepsy was a winning strategy for UCB 15
UCB's market leader status in epilepsy will be maintained by reformulations and successors to Keppra 16
Eisai 16
Eisai follows a strategy of in-licensing antiepileptic drugs 16
Key R&D company strategies 17
Reformulations 17
Extended-release formulations have dominated historical drug delivery advancements 17
Minor chemical alterations are employed to improve efficacy or reduce side effect issues 17
Indication expansion 18
Monotherapy approval remains ultimate goal but niche pediatric indications represent additional opportunities 18
Targeting additional central nervous system therapeutic indications is a common strategy 18
Bipolar disorder and neuropathic pain markets prove lucrative for antiepileptic drugs 19
2. Disease Overview - Market Potential 21
Key findings 21
Definition 22
Etiology of epilepsy 22
Diagnosis of epilepsy 23
Patient segmentation 24



Seizures are categorized according to their location of origin 24
Incidence of epilepsy 25
There is little difference in the prevalence of partial and generalized epilepsy 25
Incidence of epilepsy peaks in early and later years of life 26
Epidemiology 27
Seven major markets 28
Almost 5 million individuals are estimated to suffer from epilepsy in the seven major markets 28
Rest of the world 29
China and India both have sizable epileptic populations each in excess of 6 billion 29
Current treatment options 30
A plethora of antiepileptic drugs are available but no true broad spectrum agent exists 30
Impact of generic erosion 33
The switching of stable epilepsy patients to a generic alternative remains controversial 33
Switching between multiple generic formulations poses a danger 33
Generic antiepileptic drugs-when used correctly-offer a benefit 34
Current gold standard and comparator therapies 35
Keppra shows broad spectrum activity and a strong safety profile 35
Current market overview 38
Epilepsy market struck by US patent expiry of key brands 38
Total market volume increases despite drop in value 39
Antiepileptic drugs fall broadly into two classes based on growth rate 40
Unmet needs in epilepsy 41
Unmet need 1: efficacious treatments for refractory epilepsy 42
Unmet need 2: reduction in adverse side effects 43
Unmet need 3: greater understanding of pediatric epilepsy 45
Unmet need 4: greater treatment options for elderly patients 45
Unmet need 5: compliance 46
Target product profile versus current level of attainment 46
3. R&D Approach 49
Key findings 49
Clinical trial design in epilepsy 50
'Add-on' studies are the mainstay of clinical trial design 50
Clinical trial endpoints in epilepsy 51
Other measures focus on wider aspects of life quality 51
Post-marketing studies are important for detecting rare adverse events 52
Key difficulties in epilepsy clinical trials 53
Heterogeneity of disease 53
Wide use of patients' self-reporting 53
Applicability of trial results to the elderly population 53
Japanese clinical trials 53
Changing clinical trials methods contribute to a chasm between Japanese and Western epilepsy markets 53
Clinical trial design guidance from the EMA 54
The typical Phase III clinical trial 55
4. Pipeline Analysis & Forecasts: Ion channel modulators 56
Key findings 56
Overview for ion channel modulators 57
Pipeline summary 57
Comparative forecasts 59
Stedesa/Zebinix (eslicarbazepine acetate, Sepracor/Eisai/Bial Group) 60
Drug overview 60



US approval expected to follow 2009 EU approval 60
Drug profile 61
Clinical trial data 61
Stedesa has demonstrated impressive efficacy in reducing partial-onset seizures in refractory patients 61
SWOT analysis 63
Datamonitor's drug assessment scorecard for Stedesa 63
Clinical and commercial attractiveness 65
Despite strong trial results, Stedesa may suffer from heavy competition and the lack of distinction from the other dibenzazepines 65
Satisfaction of unmet needs 66
Stedesa will offer clear benefit should trial results transpire in practice 66
Forecasts to 2019 67
Stedesa set to achieve significant commercial success, dependent on monotherapy approval 67
Retigabine (D-23129, Valeant Pharmaceuticals/GlaxoSmithKline) 68
Drug overview 68
First-in-class ion channel modulator retigabine is pending approval in US and Europe 68
Drug profile 69
Despite high discontinuation rate, retigabine responded "almost ideally" in Phase III clinical trials 69
SWOT analysis 71
Datamonitor's drug assessment scorecard for retigabine 72
High incidence of minor side effects and three-times daily dosing offsets promising efficacy 73
Retigabine offers benefit for treatment-refractory patients 74
Sizable market share for retigabine despite use being limited to adjunctive therapy 74
Epliga (controlled-release oxcarbazepine, Supernus Pharmaceuticals) 76
Drug overview 76
Supernus claims alleviation of side effects and more convenient dosing for Epliga over Trileptal 76
Drug profile 77
Lack of publicly available clinical data for Epliga 77
SWOT analysis 79
Datamonitor's drug assessment scorecard for Epliga 80
Epliga's appeal is heavily affected by lack of novelty and strong competition 81
Epliga provides little breakthrough in the current treatment paradigm 82
Epliga to occupy small niche in market 82
Other drugs in ion channel modulation 84
Captisol-enabled fosphenytoin (CyDex Pharmaceuticals) 84
Late-stage development compounds recently discontinued 84
Comfyde (carisbamate, Johnson & Johnson) 84
Key early-stage compounds in ion channel modulation 85
ICA-105665 (Icagen) 85
Retigabine MR (Valeant Pharmaceuticals) 85
Elpetrigine (JZP-4, Jazz Pharmaceuticals) 85
5. Pipeline Analysis & Forecasts: Glutamate modulators 86
Key findings 86



Overview for glutamate receptor modulators 87
Pipeline summary 87
Comparative forecast 89
Perampanel (E2007, Eisai) 90
Drug overview 90
Global development of novel AMPA receptor antagonist perampanel in full swing 90
Drug profile 91
Strong efficacy data but safety results conspicuous by their absence 91
SWOT analysis 93
Datamonitor's drug assessment scorecard for perampanel 94
Perampanel is commercially appealing but the spotlight remains on its safety 95
Perampanel seeks to address efficacy among refractory patients 96
Steady uptake of perampanel helped by geographical expansion 96
Other drugs in glutamate modulation 97
Topiramate reformulations 97
Talampanel (Eli Lilly, Teva Pharmaceuticals) 98
Key early-stage compounds in glutamate modulation 98
BGG492 (Novartis) 98
6. Pipeline Analysis & Forecasts: GABA modulators 99
Key findings 99
Overview for GABA receptor modulation 100
Pipeline summary 101
Ganaxolone (Marinus Pharmaceuticals) 103
Drug overview 103
Innovative neurosteroid has potential broad-spectrum efficacy in epilepsy 103
Drug profile 104
Synthetic neurosteroid ganaxolone is well tolerated 104
SWOT analysis 106
Datamonitor's drug assessment scorecard for ganaxolone 107
Novelty should entice potential partners 108
Ganaxolone shows a strong safety profile and may hold promise for refractory patients 109
Secondary indication to boost ganaxolone uptake 109
DP-VPA 110
Key early-stage compounds in GABA modulation 111
T2007 (sodium diphenyl barbiturate, Taro Pharmaceuticals) 111
7. Pipeline Analysis & Forecasts: Other antiepileptic drugs 112
Key findings 112
Overview for other antiepileptic drugs 113



Rikelta (brivaracetam, UCB) 115
Drug overview 115
Rikelta is a second-generation SV2A ligand 115
Drug profile 116
Rikelta's progress slowed by mixed Phase III trial results 116
SWOT analysis 118
Datamonitor's drug assessment scorecard for Rikelta 119
Rikelta will benefit from the positive image of UCB among neurologists, but needs to differentiate from Keppra 120
Further clinical trials will expose Rikelta's potential in refractory patients 121
Strong sales but Rikelta's potential not fully realized 122
Seletracetam (UCB) 123
Key other early-stage compounds 123
VX-765 (Vertex Pharmaceuticals) 123
JNJ-26489112 (Johnson & Johnson) 124
YKP3089 (SK Life Science) 124
8. Pipeline Analysis & Forecasts: Acute epilepsy treatments 125
Key findings 125
Overview of acute epilepsy management 126
Acute seizures are a serious medical crisis 126
Gold standard for acute epilepsy management 126
Diastat (diazepam rectal gel, Valeant) 126
Unmet need in acute treatment of epilepsy 127
Undesirable delivery of diazepam represents an unmet need in the acute setting 127
Alternative methods for drug delivery 128
Intranasal delivery is convenient, easy-to-use, effective and fast-acting 128
Auto-injectors provide a reliable intramuscular route 128
ITI-111 (midazolam intranasal, Ikano Therapeutics) 131
Drug overview 131
Datamonitor drug assessment scorecard for ITI-111 132
First-to-market ITI-111 to experience strong uptake 132
JZP-8 (clonazepam intranasal, Jazz Pharmaceuticals) 133
Drug overview 133
Datamonitor drug assessment scorecard for JZP-8 134
Second-best for alternative intranasal treatment 135
Vanquix (diazepam auto-injection, King Pharmaceuticals) 136
Drug overview 136
Datamonitor's drug assessment scorecard for Vanquix 137
Success of Vanquix dependent on caregiver appeal of intramuscular injection 137
9. Innovative Early-Stage Approaches 139



Key findings 139
Medical devices in epilepsy 140
Vagus nerve stimulation 140
Cyberonics has produced the pioneering medical device in epilepsy 140
Deep brain stimulation of thalamus 141
Medtronic's device is nearing FDA approval 141
Responsive neurostimulation 142
Innovative new system responds only to abnormal electric activity in addition to providing diagnostic information 142
Intracranial drug delivery 142
Targeted drug delivery could reduce broad side-effects associated with current drug therapies 142
Future direction of epilepsy pharmacotherapy 143
Metabolic regulation provides novel mode of action for small molecules 143
2-deoxy-D-glucose (NeuroGenomeX) 143
Gene therapy can capitalize on endogenous seizure control systems 145
Galanin (Asklepios BioPharmaceutical) 145
Neuropeptide Y (Neurologix) 146
Neuropeptides can be modified to improve pharmacokinetic profile 146
NAX-5055 (NeuroAdjuvants) 146
Adenosine-releasing implants 146
Localized delivery avoids systemic side effects 146
Bibliography 148
Journal articles and conference abstracts 148
Websites 156
Datamonitor reports 158
APPENDIX 159
Methodology 159
Epidemiology estimate 159
Definition of epilepsy market 159
Product forecasts 160
Sales calculations 160
Definition of a standard unit 160
Datamonitor's drug assessment scorecard 161
Contributing experts 162
About Datamonitor 163
About Datamonitor Healthcare 163
About the Disease analysis team 163
Datamonitor consulting 164
Disclaimer 166
List of Tables
Table 1: Key late-stage pipeline products in development for epilepsy, 2010 8
Table 2: Investigated epilepsy types for key pipeline antiepileptic drugs, 2010 11
Table 3: Sales forecasts for pipeline products in epilepsy in the seven major markets ($m), 2010-19 12
Table 4: UCB's antiepileptic drug portfolio, 2010 15
Table 5: Eisai's antiepileptic drug portfolio, 2010 16
Table 6: Different seizure types and their typical characteristics 24
Table 7: Prevalence of active epilepsy in the seven major markets (000s), 2010 28
Table 8: Prevalence of epilepsy in the BRIC nations, Turkey and Canada (000s), 2010 29
Table 9: Leading treatment options for epilepsy, 2010 31
Table 10: Total healthcare costs of topiramate users, 2009 34
Table 11: Keppra (levetiracetam) - drug profile, 2010 36



Table 12: Ability of current class comparator to meet unmet needs in epilepsy, 2010 48
Table 13: Typical Phase III clinical trial design in epilepsy 55
Table 14: Ion channel modulator drugs in late-stage development for epilepsy, 2010 59
Table 15: Sales forecasts for ion channel modulators in development for epilepsy in the seven major markets ($m), 2010-19 59
Table 16: Stedesa - drug profile, 2010 61
Table 17: Phase III clinical trials for eslicarbazepine acetate, 2008 62
Table 18: Datamonitor's drug assessment scorecard for Stedesa in epilepsy, 2010 65
Table 19: Sales forecasts for Stedesa in the seven major markets ($m), 2010-19 67
Table 20: Impacting factors on the revenue of Stedesa, 2010-19 68
Table 21: Retigabine - drug profile, 2010 69
Table 22: Phase III trial data for retigabine, 2008 70
Table 23: Datamonitor's drug assessment scorecard for retigabine in epilepsy, 2010 73
Table 24: Sales forecasts for retigabine in the seven major markets ($m), 2010-19 75
Table 25: Impacting factors on the revenue of retigabine, 2010-19 75
Table 26: Epliga - drug profile, 2010 77
Table 27: Key facts: Phase III trial of Epliga, 2010 78
Table 28: Datamonitor's drug assessment scorecard for Epliga in epilepsy, 2010 81
Table 29: Sales forecasts for Epliga in the seven major markets ($m), 2010-19 83
Table 30: Impacting factors on the revenue of Epliga, 2010-19 83
Table 31: Glutamate modulator drugs in late-stage development for epilepsy, 2010 89
Table 32: Sales forecasts for glutamate modulators in development for epilepsy in the seven major markets ($m), 2010-19 89
Table 33: Perampanel - drug profile, 2010 91
Table 34: Key facts: Phase III trial of perampanel, 2010 92
Table 35: Datamonitor's drug assessment scorecard for perampanel in epilepsy, 2010 95
Table 36: Sales forecasts for perampanel in the seven major markets ($m), 2010-19 96
Table 37: Impacting factors on the revenue of perampanel, 2010-19 97
Table 38: GABA modulator drug in late-stage development for epilepsy, 2010 102
Table 39: Sales forecasts for GABA modulators in development for epilepsy in the seven major markets ($m), 2010-19 102
Table 40: Ganaxolone - drug profile, 2010 104
Table 41: Key facts: Phase II trial of ganaxolone, 2010 105
Table 42: Datamonitor's drug assessment scorecard for ganaxolone in epilepsy, 2010 108
Table 43: Sales forecasts for ganaxolone in the seven major markets ($m), 2010-19 110
Table 44: Impacting factors on the revenue of ganaxolone, 2010-19 110
Table 45: Other drugs in late-stage development for epilepsy, 2010 114
Table 46: Sales forecasts for other drugs in development for epilepsy in the seven major markets ($m), 2010-19 114
Table 47: Rikelta - drug profile, 2010 116
Table 48: Phase II clinical trials for Rikelta, 2006 117
Table 49: Datamonitor's drug assessment scorecard for Rikelta in epilepsy, 2010 120
Table 50: Sales forecasts for Rikelta in the seven major markets ($m), 2010-192010-19 122
Table 51: Impacting factors on the revenue of Rikelta, 2010-19 123
Table 52: Diastat (diazepam rectal gel) - drug profile, 2010 127
Table 53: Treatments in late-stage development for acute epilepsy management, 2010 130
Table 54: Sales forecasts for pipeline products in epilepsy in the US ($m), 2010-19 130
Table 55: Datamonitor's drug assessment scorecard for ITI-111 in acute epilepsy, 2010 132
Table 56: Sales forecasts for ITI-111 in the seven major markets ($m), 2010-19 133
Table 57: Impacting factors on the revenue of ITI-111, 2010-19 133
Table 58: Datamonitor's drug assessment scorecard for JZP-8 in acute epilepsy, 2010 134
Table 59: Sales forecasts for JZP-8 in the seven major markets ($m), 2010-19 135
Table 60: Impacting factors on the revenue of JZP-8, 2010-19 135
Table 61: Datamonitor's drug assessment scorecard for Vanquix in acute epilepsy, 2010 137



Table 62: Sales forecasts for Vanquix in the seven major markets ($m), 2010-19 138
Table 63: Impacting factors on the revenue of Vanquix, 2010-19 138
Table 64: ICD-10 codes used to define the epilepsy market 159
Table 65: Datamonitor's drug assessment parameters for key late-stage epilepsy pipeline therapies 161
Table 66: Datamonitor's drug assessment parameters for key late-stage acute epilepsy pipeline therapies 162
List of Figures
Figure 1: Late-stage epilepsy pipeline products by mode of action, 2010 9
Figure 2: Typical modes of action in epilepsy pharmacotherapy 10
Figure 3: Epilepsy-specific sales, historical and forecast to 2019, across the seven major markets 13
Figure 4: Datamonitor's pipeline assessment summary for epilepsy, 2010 14
Figure 5: Additional indications of key approved and pipeline antiepileptic drugs, 2010 19
Figure 6: Incidence of epilepsy by seizure type 26
Figure 7: Incidence of epilepsy in different age groups 27
Figure 8: Epilepsy population in Brazil, India, China and the US, 2010 30
Figure 9: Epilepsy-specific sales value ($ billion) in the seven major markets by region, 2005-2009 38
Figure 10: Epilepsy-specific sales volume (billion SUs) in the seven major markets by region, 2005-2009 39
Figure 11: Epilepsy market mean prices split by region in the seven major markets, 2005-2009 40
Figure 12: Performance of the top 10 brands in the seven major markets ($m), 2005-09 41
Figure 13: Key unmet needs for epilepsy, 2010 42
Figure 14: Ion channel modulators as antiepileptic drugs 57
Figure 15: Datamonitor's pipeline assessment summary for ion channel modulators in epilepsy, 2010 58
Figure 16: Stedesa - SWOT analysis, 2010 63
Figure 17: Datamonitor's drug assessment summary for Stedesa in epilepsy, 2010 64
Figure 18: Retigabine - SWOT analysis, 2010 71
Figure 19: Datamonitor's drug assessment summary for retigabine in epilepsy, 2010 72
Figure 20: Epliga - SWOT analysis, 2010 79
Figure 21: Datamonitor's drug assessment summary for Epliga in epilepsy, 2010 80
Figure 22: Glutamate receptor modulators as antiepileptic drugs 87
Figure 23: Datamonitor's drug assessment summary for glutamate modulators in epilepsy, 2010 88
Figure 24: Perampanel - SWOT analysis, 2010 93
Figure 25: Datamonitor's drug assessment summary for perampanel in epilepsy, 2010 94
Figure 26: GABA receptor modulators as antiepileptic drugs 100
Figure 27: Datamonitor's drug assessment summary for ganaxolone in epilepsy, 2010 101
Figure 28: Ganaxolone - SWOT analysis, 2010 106
Figure 29: Datamonitor's drug assessment summary for ganaxolone in epilepsy, 2010 107
Figure 30: Datamonitor's drug assessment summary for other drugs in development for epilepsy, 2010 113
Figure 31: Rikelta - SWOT analysis, 2010 118
Figure 32: Datamonitor's drug assessment summary for Rikelta in epilepsy, 2010 119
Figure 33: Datamonitor's pipeline assessment summary for acute antiepileptic therapies in epilepsy, 2010 129
Figure 34: Possible inhibition of kindling progression by 2-deoxy-D-glucose in epilepsy 144
Figure 35: Design of adenosine-releasing implants 147



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Pipeline Insight: Epilepsy - Past successes hard to emulate in highly genericized market

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Pipeline Insight: Epilepsy - Past successes hard to emulate in highly genericized market