gbihc325mr epilepsy therapeutics in major developed ... · 2.11 non-pharmacological management ......

Epilepsy Therapeutics in Major Developed Markets to 2019 New AEDs with Novel Mechanisms of Action Signal a Shift in Treatment Patterns

GBI Research Report Guidance

© GBI Research. This is a licensed product and is not to be photocopied GBIHC325MR/ Published MAR 2014 Page 2

GBI Research Report Guidance

Chapter two gives an overview of epilepsy epidemiology, pathogenesis, diagnosis, and the therapeutic unmet need of the indication.

Chapter three gives an overview of the treatments that are currently available for epilepsy, including all first, second and third-line therapies as well as an outline of their revenue, efficacy, safety, and future prospects.

Chapter four provides in-depth analysis of the pipeline drug analysis of the epilepsy therapeutic pipeline and, subsequent to this, an overview of four promising pipeline molecules in later-stage trials, which look set to make an impact on the market.

Chapter five provides revenue forecasts for the major developed markets of US, UK, France, Germany, Italy, Spain, Japan and Canada until 2019.

Chapter six provides an overview of notable co-development and licensing deals in the epilepsy market.

© GBI Research. This is a licensed product and is not to be photocopied GBIHC325MR/ Published MAR 2014

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Executive Summary

Executive Summary

Growth in Epilepsy Market is Expected to be Modest During 2012–2019 Period

The epilepsy therapeutic market in the eight major developed markets of US, UK, France, Germany, Italy, Spain, Japan and Canada was estimated to value $XX billion in 2012. The market is expected to grow at a modest compound annual growth rate of XX% to reach $XX billion over the 2012–2019 period. US held the largest share of XX% followed by Germany at XX% and Japan at XX% in 2012. Growth in these markets will be mostly driven by the revenues of new Anti-Epileptic Drugs (AED) that were approved during the last five years, however growth is expected to be somewhat limited by the recent patent expiration of key AEDs such as Keppra (levetiracetam) and Lamictal (lamotrigine). In 2012, the epilepsy market was dominated by first- and second-generation AEDs with market shares of over XX% of the total. Three new AEDs have been approved in the US since 2012, including, Trobalt (ezogabine, 2012), Aptiom (eslicarbazepine acetate, 2013), and Fycompa (perampanel, 2013). Another AED, brivaracetam is expected to be launched during the forecast period, in total, these new AEDs are expected to gain a combined share of around XX% of the major developed markets by 2019. The current prescribing patterns are expected to remain stable during the forecast period with minor fluctuations due to the launch of new drugs.

It is estimated that there are around XX million epilepsy sufferers, worldwide. Although roughly XX% of cases are in developing countries, the major developed markets also have a high burden of this brain disorder with a prevalence population of around XX million people in 2012. It is estimated that only around XX–XX% of patients respond to treatment with existing AEDs leaving an unmet need of XX–XX% of refractory epilepsy cases. The epilepsy treatment population in 2012 was estimated to be XX million and this expected to reach XX million by 2019.

Epilepsy Therapeutics, Major Developed Markets, Treatment Usage Pattern and Market Size, 2012–2019

A) Treatment usage pattern

B) Market size

2012 2013 2014 2015 2016 2017 2018 2019

Patie

nts

(mill

ion)

Prevalence population Treatment population

2012 2013 2014 2015 2016 2017 2018 2019

Mar

ket s

ize

($bn

)

Low variance Medium variance High variance Projected

Source: GBI Research, Proprietary Marketed Products Database

Epilepsy market is still dominated by the first- and second-generation AEDs that make up to over XX% of the market share.


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Table of Contents

1 Table of Contents 1 Table of Contents ................................................................................................................................. 5

1.1 List of Tables ............................................................................................................................. 7 1.2 List of Figures............................................................................................................................ 7

2 Introduction......................................................................................................................................... 9 2.1 Disease Overview...................................................................................................................... 9 2.2 Epidemiology ............................................................................................................................ 9 2.3 Symptoms ...............................................................................................................................10 2.4 Etiology ...................................................................................................................................11 2.5 Pathophysiology ......................................................................................................................12 2.6 Co-morbidities/Complications ..................................................................................................12 2.7 Diagnosis .................................................................................................................................12 2.8 Prognosis .................................................................................................................................13 2.9 Treatment Efficacy ...................................................................................................................13 2.10 Treatment Options ..................................................................................................................13

2.10.1 Ion Channel Modulators ...................................................................................................14 2.10.2 GABA-ergic Facilitation.....................................................................................................14 2.10.3 Excitatory Amino Acid Inhibitors .......................................................................................15 2.10.4 Synaptic Modulators ........................................................................................................15

2.11 Non-pharmacological Management..........................................................................................15 2.11.1 Lobectomy and Lesionectomy ...........................................................................................15 2.11.2 Ketogenic Diet and Modified Atkins Diet ...........................................................................15 2.11.3 Vagus Nerve Stimulation ..................................................................................................16

3 Epilepsy Therapeutic Landscape ..........................................................................................................17 3.1 Overview .................................................................................................................................17 3.2 Lyrica (pregabalin) ...................................................................................................................17 3.3 Lamictal (lamotrigine) ..............................................................................................................18 3.4 Keppra (levetiracetam) ............................................................................................................19 3.5 Zonegran (zonisamide) .............................................................................................................21 3.6 Vimpat (lacosamide) ................................................................................................................22 3.7 Aptiom/Zebinix (eslicarbazepine acetate) .................................................................................23 3.8 Fycompa (perampanel) ............................................................................................................24 3.9 Trobalt/Potiga (ezogabine/retigabine) ......................................................................................25 3.10 Banzel/Inovelon (rufinamide) ...................................................................................................25 3.11 Comparative Efficacy and Safety of Marketed Products ............................................................26

4 Pipeline for Epilepsy Therapeutics .......................................................................................................29 4.1 Overall Pipeline........................................................................................................................29 4.2 Pipeline by Mechanism of Action..............................................................................................31 4.3 Clinical Trials ............................................................................................................................32

4.3.1 Failure Rate .....................................................................................................................32 4.3.2 Patient Enrolment and Clinical Trial Size............................................................................34 4.3.3 Clinical Trial Duration .......................................................................................................35

4.4 Promising Pipeline Candidates .................................................................................................37 4.4.1 Brivaracetam – UCB .........................................................................................................38 4.4.2 Ganaxolone – Marinus Pharmaceuticals ...........................................................................38

5 Epilepsy Therapeutics Market Forecast to 2019 ...................................................................................39 5.1 Geographical Markets ..............................................................................................................39

5.1.1 Major Developed Markets ................................................................................................39 5.1.2 The US .............................................................................................................................40 5.1.3 Top Five EU Countries .......................................................................................................43 5.1.4 Japan ...............................................................................................................................46


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Table of Contents

5.1.5 Canada ............................................................................................................................48 5.2 Drivers and Barriers .................................................................................................................50

5.2.1 Drivers .............................................................................................................................50 5.2.2 Barriers ............................................................................................................................50

6 Deals and Strategic Consolidations ......................................................................................................52 6.1 Deals Analysis ..........................................................................................................................52 6.2 Research and Development Co-development Agreements ........................................................54 6.3 Research and Development Licensing Agreements ...................................................................55

7 Appendix ............................................................................................................................................57 7.1 Abbreviations ..........................................................................................................................57 7.2 References ..............................................................................................................................58 7.3 References for Heat Maps ........................................................................................................62 7.4 Pipeline Products by Phase.......................................................................................................63

7.4.1 Discovery .........................................................................................................................63 7.4.2 Preclinical ........................................................................................................................63 7.4.3 IND-filed and Phase 0 .......................................................................................................64 7.4.4 Phase I .............................................................................................................................64 7.4.5 Phase II ............................................................................................................................64 7.4.6 Phase III ...........................................................................................................................65 7.4.7 Pre-registration ................................................................................................................65

7.5 Market Forecasting Data Tables to 2019 ...................................................................................66 7.5.1 Major Developed Markets ................................................................................................66 7.5.2 US....................................................................................................................................66 7.5.3 UK ...................................................................................................................................66 7.5.4 France .............................................................................................................................67 7.5.5 Germany ..........................................................................................................................67 7.5.6 Italy .................................................................................................................................67 7.5.7 Spain ...............................................................................................................................68 7.5.8 Japan ...............................................................................................................................68 7.5.9 Canada ............................................................................................................................68

7.6 Research Methodology ............................................................................................................69 7.6.1 Coverage .........................................................................................................................69 7.6.2 Secondary Research .........................................................................................................69 7.6.3 Primary Research .............................................................................................................69 7.6.4 Therapeutic Landscape .....................................................................................................70 7.6.5 Geographical Landscape ..................................................................................................73 7.6.6 Pipeline Analysis...............................................................................................................73

7.7 Expert Panel Validation ............................................................................................................73 7.8 Contact Us ...............................................................................................................................73 7.9 Disclaimer................................................................................................................................73


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Table of Contents

1.1 List of Tables Table 1: Epilepsy Therapeutics, Global, Types of Seizures, 2013 ............................................................. 9 Table 2: Epilepsy Therapeutics, Heat Maps for Efficacy and Safety of Marketed Products, References....62 Table 3: Epilepsy Therapeutics, Global, Pharmaceutical Pipeline (Discovery), 2013 ................................63 Table 4: Epilepsy Therapeutics, Global, Pharmaceutical Pipeline (Preclinical), 2013 ...............................63 Table 5: Epilepsy Therapeutics, Global, Pharmaceutical Pipeline (IND/CTA-filed), 2013 ..........................64 Table 6: Epilepsy Therapeutics, Global, Pharmaceutical Pipeline (Phase I), 2013 ....................................64 Table 7: Epilepsy Therapeutics, Global, Pharmaceutical Pipeline (Phase II), 2013 ...................................64 Table 8: Epilepsy Therapeutics, Global, Pharmaceutical Pipeline (Phase III), 2013 ..................................65 Table 9: Epilepsy Therapeutics, Global, Pharmaceutical Pipeline (Pre-registration), 2013 .......................65 Table 10: Epilepsy Therapeutics, Major Developed Markets, Market Forecast, 2012–2019 ......................66 Table 11: Epilepsy Therapeutics, US, Market Forecast, 2012–2019 ..........................................................66 Table 12: Epilepsy Therapeutics, UK, Market Forecast, 2012–2019 ..........................................................66 Table 13: Epilepsy Therapeutics, France, Market Forecast, 2012–2019 ....................................................67 Table 14: Epilepsy Therapeutics, Germany, Market Forecast, 2012–2019 ................................................67 Table 15: Epilepsy Therapeutics, Italy, Market Forecast, 2012–2019........................................................67 Table 16: Epilepsy Therapeutics, Spain, Market Forecast, 2012–2019 ......................................................68 Table 17: Epilepsy Therapeutics, Japan, Market Forecast, 2012–2019 .....................................................68 Table 18: Epilepsy Therapeutics, Canada, Market Forecast, 2012–2019 ...................................................68


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Table of Contents

1.2 List of Figures Figure 1: Epilepsy Therapeutics, Epidemiology, Major Developed Markets, 2012 ....................................10 Figure 2: Epilepsy Therapeutics, Major Developed Markets, Approved Anti-epileptic Drugs, 2013 ...........14 Figure 3: Epilepsy Therapeutics, Lyrica, Global, Revenue ($bn), 2013 ......................................................18 Figure 4: Epilepsy Therapeutics, Lamictal, Global, Revenue ($m), 2009–2013 .........................................19 Figure 5: Epilepsy Therapeutics, Keppra, Global, Revenue ($bn), 2009–2013 ..........................................20 Figure 6: Epilepsy Therapeutics, Zonegran, Global, Revenue ($m), 2009–2013 ........................................21 Figure 7: Epilepsy Therapeutics, Vimpat, Global, Revenue ($m), 2009–2013 ...........................................23 Figure 8: Epilepsy Therapeutics, Global, Comparative Safety and Efficacy of Marketed Products (Heat

Map), 2013 .............................................................................................................................27 Figure 9: Epilepsy Therapeutics, Global, Overall Pipeline Analysis, 2013 ..................................................30 Figure 10: Epilepsy Therapeutics, Global, Pipeline Analysis, by Mechanism of Action, 2013 .......................31 Figure 11: Epilepsy Therapeutics, Global, Pipeline, Clinical Trial Failure Rate, 2013 ...................................33 Figure 12: Epilepsy Therapeutics, Global, Pipeline, Clinical Trial Size, 2013 ................................................35 Figure 13: Epilepsy Therapeutics, Global, Pipeline, Clinical Trial Duration, 2013 ........................................37 Figure 14: Epilepsy Therapeutics, Major Developed Markets, Treatment Usage Pattern and Market Size,

2012–2019 .............................................................................................................................40 Figure 15: Epilepsy Therapeutics, US, Treatment Usage Pattern, ACoT and Market Size, 2012–2019 .........42 Figure 16: Epilepsy Therapeutics, Top Five EU Countries, Treatment Patterns (‘000), 2012–2019 ..............43 Figure 17: Epilepsy Therapeutics, Top Five EU Countries, Annual Cost of Treatment ($), 2012–2019 .........44 Figure 18: Epilepsy Therapeutics, Top Five EU Countries, Market Size ($m), 2012–2019 ............................45 Figure 19: Epilepsy Therapeutics, Japan, Treatment Usage Pattern, ACoT and Market Size, 2012–2019 .....47 Figure 20: Epilepsy Therapeutics, Canada, Market Size, 2012–2019 ..........................................................49 Figure 21: Epilepsy Therapeutics, Deals by Region, Value and Year, 2006–2013 ........................................52 Figure 22: Epilepsy Therapeutics, Deals by Molecule Type and Mechanism of Action, 2006–2013 .............53 Figure 23: Epilepsy Therapeutics, Co-development Deals, Territory, 2006–2013 .......................................54 Figure 24: Epilepsy Therapeutics, Licensing Deals, by Territory, 2006–2013 ..............................................55 Figure 25: GBI Research Market Forecasting Model .................................................................................72


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Introduction

2 Introduction 2.1 Disease Overview Epilepsy is a group of disorders characterized by the repeated occurrence of convulsions or seizures as a result of abnormal electrical activity originating in the brain. Although up to XX% of people worldwide have one seizure during their lifetime, a person is only considered to have epilepsy when they have had two or more unprovoked seizures (WHO, 2009). Based on the type of behavior and brain activity, seizures are divided into two broad categories: generalized and partial (also called local or focal). Generalized seizures are produced by electrical impulses throughout the entire brain, whereas partial seizures are produced (at least initially) by electrical impulses in a relatively small part of the brain. The part of the brain generating the seizures is sometimes called the focus. Around XX% of seizures are partial or focal seizures. Other forms of epilepsy include Lennox-Gastaut Syndrome (LGS) and Rasmussen's encephalitis, which develop in childhood. LGS is a severe form of epilepsy that leads to several different types of seizures, including atonic seizures, which cause sudden falls. Rasmussen's encephalitis is a progressive type of epilepsy in which half of the brain shows continual inflammation.

Table 1: Epilepsy Therapeutics, Global, Types of Seizures, 2013

Generalized seizures Partial seizures

Source: NHS, 2013

2.2 Epidemiology The overall prevalence of active epilepsy in the key developed markets is estimated to be XX million and is expected to increase at a Compound Annual Growth Rate (CAGR) of XX% until 2019 when it will reach XX million. Active epilepsy in patients is defined as the occurrence of at least one unprovoked seizure during the past one year or if a patient currently requires seizure medication. The incidence of epilepsy is much higher in the developing world at XX–XX per XX than in the developed world at XX–XX per XX (Shih-Hui, 2004). It is estimated that about 80% of the global epilepsy patient population is from the developing world (WHO, 2012). In the US, approximately XX new cases of seizures and epilepsy occur each year and the incidence rate is higher in children and the elderly compared with adults under XX years of age. The prevalence of epilepsy in Europe is estimated to be higher than in the US at XX per XX with approximately six million people in Europe living with active epilepsy (WHO, 2011). Incidence in Japan is estimated to be XX per XX population and prevalence is similar to Europe with XX cases per XX (WHO, 2004). Canada has an overall epilepsy incidence of XX–XX per XX population and the active epilepsy prevalence is reported to be XX–XX per XX persons or approximately XX% of Canadian population (Theodore et al, 2006; Epilepsy Canada, 2013). The treatment gap in epilepsy (proportion of people with epilepsy who require treatment but do not receive it), varies widely among European countries with XX% for the UK, XX% for France, XX% for Spain compared with XX–XX% for the US (Meyer et al, 2009). The treatment gap is much higher in developing countries such as India (XX%) and China (XX%). The treatment population is expected to grow at a CAGR of XX% in the eight developed markets analyzed in this report increasing from XX million in 2012 to XX million by 2019.

The treatment gap in epilepsy varies widely amongst the European countries.

Pipeline for Epilepsy Therapeutics


4 Pipeline for Epilepsy Therapeutics 4.1 Overall Pipeline The epilepsy pipeline has very few promising drugs in late-stage clinical trials, since most of the most promising molecules have recently received approvals. Many recent approvals, and a number of promising candidates still currently in the pipeline, are structural analogs of existing AEDs, including the recently approved eslicarbazepine acetate, which is a third-generation carbamazepine, and brivaracetam, the most promising of the current Phase III molecules, which is an analog of levetiracetam.

However, the developmental pipeline for AEDs is currently not very strong. A lower number of novel drugs in the late stages of development, as most of the candidates are approved AEDs that are currently under investigation for extension of indications. From a total of XX pipeline products in active development, around XX% are in the Preclinical stage, XX% are in Phase I, XX% are in Phase II, and XX% are in Phase III (Figure 9, Panel A). Almost all the pipeline at various stages is dominated by small molecules, which comprise XX% of the overall pipeline, while just XX candidates, or XX%, are peptides and there is just one gene therapy (Figure 9, Panel C). The route of administration of the pipeline drugs is predominantly oral (XX%, XX molecules), although some are administered intravenously (XX%, XX molecules) and others nasally (XX% or XX molecules). The share of all other routes of administration is displayed in the figure below (Figure 9, Panel C). As displayed in Figure 9, Panel B, a large proportion (XX%) of pipeline molecules are novel drug candidates. Of XX active molecules, XX% (or XX molecules) are generics and XX% (or XX molecules) are already marketed for other indications (repositioning).

Brivaracetam, which is the only promising novel drug in Phase III, has a similar mechanism of action as that of levetiracetam.

Pipeline for Epilepsy Therapeutics


Figure 9: Epilepsy Therapeutics, Global, Overall Pipeline Analysis, 2013

Stage of development B) Program typeA)

Route of administrationC) Molecule typeD)

Generic Novel Repositioning

Oral Not disclosed IntravenousNasal Intramuscular SubcutaneousParenteral Intraperitoneal

Small molecule Gene therapyPeptide Not disclosed

Discovery PreclinicalIND/CTA-filed Phase IPhase II Phase IIIPre-registration

Source: GBI Research, Proprietary Pipeline Products Database

IND: Investigational New Drug; CTA: Clinical Trial Applications

Epilepsy Therapeutics Market Forecast to 2019


5.1.3.2 Annual Cost of Therapy

The cost of prescription drugs varies widely across Europe and is highest in Germany (SNF, 2012). The average ACoT in 2012 was found to be highest in Germany at $XX followed by Italy at $XX. The average ACoT was lowest in France at $XX. Spain is expected to post the highest growth rate in ACoT at a CAGR of XX% during the 2012–2019 period. In Germany, ACoT is expected to grow at a low CAGR of XX% during the forecast period due to the pricing regulations implemented since 2011 under the Act on the Reform of the Market for Medicinal Products (also called AMNOG) and also due to the generic erosion of drugs that became off-patent in the last few years. Generic substitution is higher in Germany compared with some other European countries covered in the report. In contrast, the generic substitution is much lower in France and Spain which are expected to post a higher growth during the 2012–2019 forecast period (XX% and XX% respectively).

Prescription patterns in the top five EU countries are similar to that of the US with first-generation AEDs such as phenytoin, (sodium) valproate and carbamazepine taking a major share of the market. The shares of second-generation AEDs, levetiracetam and lamotrigine, have increased steadily in the recent years with almost all these drugs currently having similar shares of the epilepsy market. In the UK, carbamazepine and valproate dominate the market with lamotrigine as another preferred option. Since generic erosion is expected to be lower in the UK, these prescribing patterns are expected to remain similar during the forecast period. Little impact is expected from the recent launches or promising pipeline drugs keeping the ACoT more or less stable across the European region.

Figure 17: Epilepsy Therapeutics, Top Five EU Countries, Annual Cost of Treatment ($), 2012–2019

2012 2013 2014 2015 2016 2017 2018 2019

Ann

ual c

ost o

f the

rapy

($)

UK


2012 2013 2014 2015 2016 2017 2018 2019

Annu

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($)

France


2012 2013 2014 2015 2016 2017 2018 2019

Annu

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Germany


2012 2013 2014 2015 2016 2017 2018 2019

Ann

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2012 2013 2014 2015 2016 2017 2018 2019

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Spain

Low variance Medium variance High variance Projected Source: GBI Research, Proprietary Marketed Products Database

Appendix


7 Appendix 7.1 Abbreviations 5-HT1a: 5-hydroxytryptamine

ACh: Acetylcholine

AE: Adverse Event

AED: Anti-Epileptic Drug

AMPA: Alpha-Amino-2,3-Dihydro-5-Methyl-3-Oxo-4-Isoxazolepropanoic Acid

ARS: Acute Repetitive Seizure

BID: Bis In Die (twice daily)

CAGR: Compound Annual Growth Rate

CDC: Centers for Disease Control and Prevention

CNS: Central Nervous System

CRMP-2: Collapsin Response Mediator Protein-2

EEG: Electroencephalogram

EMA: European Medicine Agency

FDA: Food and Drug Administration

fMRI: Functional Magnetic Resonance Imaging

GABA: Gamma-Aminobutyric Acid

GSK: GlaxoSmithKline

ILAE: International League Against Epilepsy

KCNQ2: potassium voltage-gated channel, Kqt-like subfamily, member 2

KCNQ3: potassium voltage-gated channel, Kqt-like subfamily, member 3

LGS: Lennox-Gastaut Syndrome

mg: milligrams

MHLW: Ministry of Health, Labor and Welfare

ml: millileter

MoA: Mechanism of Action

MRI: Magnetic Resonance Imaging

NHIS: National Health Interview Survey

NMDA: N-Methyl-D-Aspartate

PET: Positron Emission Tomography

PHN: Postherpetic Neuralgia

SPECT: Single Photon Emission Computed Tomography

SE: Status Epilectus

SUDEP: Sudden, Unexpected Death in Epilepsy

SV2A: Synaptic Vesicle Protein 2a

TID: TID: Ter In Die (thrice daily)

Appendix


ULD: Unverricht Lundborg Disease

WHO: World Health Organization

7.2 References Abou-Khalil, B (2008). Levetiracetam in the treatment of epilepsy. Neuropsychiatric Disease Treatment,

4(3): 507–523

Adams CP and Brantner VV (2010). Spending on New Drug Development. Health Economics; 19(2): 130-141

Arroyo, S et al. (2004). Pregabalin add-on treatment: a randomized, double-blind, placebo-controlled, dose-response study in adults with partial seizures. Epilepsia, 45: 20–27

Ben-Menachem, E and Falter, U (2000). Efficacy and tolerability of levetiracetam 3000 mg/d in patients with refractory partial seizures: a multicenter, double-blind, responder-selected study evaluating monotherapy. European Levetiracetam Study Group. Epilepsia, 41(10): 1,276–1,283

Ben-Menachem, E et al. (2007). Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures. Epilepsia, 48(7): 1,308–1,317

Ben-Menachem, E et al. (2010). Eslicarbazepine acetate as adjunctive therapy in adult patients with partial epilepsy. Epilepsy Research, 89(2): 278–285

Biton, V et al. (2014). Brivaracetam as adjunctive treatment for uncontrolled partial epilepsy in adults: A phase III randomized, double-blind, placebo-controlled trial. Epilepsia, 55(1): 57–66

Booth, L and Thompson, G (2010). Epilepsy statistics. Social and General Statistics, House of Common Library. Available from: http://www.parliament.uk/Templates/BriefingPapers/Pages/BPPdfDownload.aspx?bp-id=sn05691 [Accessed: January 25, 2014]

Brodie, MJ (2004). Pregabalin as Adjunctive Therapy for Partial Seizures. Epilepsia, 45(6): 19–27

Brodie, MJ et al. (2010). Efficacy and safety of adjunctive ezogabine (retigabine) in refractory partial epilepsy. Neurology, 75(20): 1,817–1,824

Canadian Epilepsy Alliance (2012). The Impact of Epilepsy in Canadians. Available from: http://epilepsyhaltonpeel.org/wp-content/uploads/2010/03/Impact-of-Epilepsy1.pdf

CDC (2012). Morbidity and Mortality Weekly Report. Centers for Disease Control and Prevention. Available from: http://www.cdc.gov/mmwr/pdf/wk/mm6145.pdf

CDC (2013). Comorbidity in Adults with Epilepsy — United States, 2010. Centers for Disease Control and Prevention. Available from: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6243a2.htm [Accessed: December 15, 2013]

Cereghino, JJ et al. (2000). Levetiracetam for partial seizures: results of a double-blind, randomized clinical trial. Neurology, 55(2): 236–242

Chung, S et al. (2010). Lacosamide as adjunctive therapy for partial-onset seizures: a randomized controlled trial. Epilepsia, 51(6): 958–967

Crawford, P et al., (2006). Are there potential problems with generic substitution of antiepileptic drugs?: A review of issues. Seizure, Vol.: 15, No.: 3, pp: 165–176

Elger, CE et al. (2009). Efficacy and safety of eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures: A randomized, double-blind, placebo-controlled, parallel-group phase III study. Epilepsia, 50: 454–463

Elger, CE et al. (2005). Pregabalin add-on treatment in patients with partial seizures: a novel evaluation of flexible-dose and fixed-dose treatment in a double-blind, placebo-controlled study. Epilepsia, 46: 1,926–1,936

Appendix


7.3 References for Heat Maps

Table 2: Epilepsy Therapeutics, Heat Maps for Efficacy and Safety of Marketed Products, References

1 Arroyo, S et al. (2004). Pregabalin add-on treatment: a randomized, double-blind, placebo-controlled, dose–response study in adults with partial seizures. Epilepsia, 45: 20–27

2 Ben-Menachem, E (2010). Eslicarbazepine acetate as adjunctive therapy in adult patients with partial epilepsy. Epilepsy Research, 89(2): 278-285

3 Ben-Menachem, E and Falter, U (2000). Efficacy and tolerability of levetiracetam 3000 mg/d in patients with refractory partial seizures: a multicenter, double-blind, responder-selected study evaluating monotherapy. European Levetiracetam Study Group. Epilepsia, 41(10): 1,276–1,283

4 Ben-Menachem, E et al. (2007. Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures. Epilepsia, 48(7): 1308–1,317

5 Beydoun, A et al. (2005). Pregabalin 1008-009 Study Group Safety and efficacy of two pregabalin regimens for add-on treatment of partial epilepsy. Neurology, 64: 475–480

6 Brodie, MJ et al. (2010). Efficacy and safety of adjunctive ezogabine (retigabine) in refractory partial epilepsy. Neurology, 75(20): 1,817–1,824

7 Cereghino, JJ et al. (2000). Levetiracetam for partial seizures: results of a double-blind, randomized clinical trial. Neurology, 55(2): 236–242

8 Chung, S et al. (2010b). Lacosamide as adjunctive therapy for partial-onset seizures: a randomized controlled trial. Epilepsia, 51(6): 958–967

9 Elger, C (2009). Efficacy and safety of eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures: A randomized, double-blind, placebo-controlled, parallel-group phase III study. Epilepsia, 50: 454–463

10 Elger, CE et al. (2005). Pregabalin add-on treatment in patients with partial seizures: a novel evaluation of flexible-dose and fixed-dose treatment in a double-blind, placebo-controlled study. Epilepsia, 46: 1,926–1,936

11 Faught, E et al. (2001). Randomized controlled trial of zonisamide for the treatment of refractory partial-onset seizures. Neurology, 57(10): 1,774–1,779.

12 French, JA (2003). Dose–response trial of pregabalin adjunctive therapy in patients with partial seizures. Neurology, 60: 1,631–1,637

13 French, JA (2012). Adjunctive perampanel for refractory partial-onset seizures. Randomized phase III study 304. Neurology, 79(6): 589–596

14 French, JA et al (2011). Randomized, double-blind, placebo-controlled trial of ezogabine (retigabine) in partial epilepsy. Neurology, 76(18): 1,555–1,563

15 French, JA et al. (2013). Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: Results of randomized global phase III study 305. Epilepsia, 54: 117–125

16 Gil-Nagel, A et al. (2009). Efficacy and safety of 800 and 1200 mg eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures. Acta Neurologica Scandinavica, 120: 281–287

17 Halász, P et al. (2009. Adjunctive lacosamide for partial-onset seizures: Efficacy and safety results from a randomized controlled trial. Epilepsia, 50(3): 443–453

18 Krauss GL, et al. (2012). Randomized phase III study 306: adjunctive perampanel for refractory partial-onset seizures. Neurology, 78(18): 1,408–1,415.

19 Porter, RJ et al. (2007). Randomized, multicenter, dose-ranging trial of retigabine for partial-onset seizures. Neurology, 68(15): 1,197–1,204.

20 Schmidt D, et al. (1993). Zonisamide for add-on treatment of refractory partial epilepsy: a European double-blind trial. Epilepsy Research, 15: 67–73

21 Shorvon, SD et al. (2000). Multicenter double-blind, randomized, placebo-controlled trial of levetiracetam as add-on therapy in patients with refractory partial seizures. European Levetiracetam Study Group. Epilepsia, 41(9): 1,179-1,186

Source: GBI Research

Appendix


7.4 Pipeline Products by Phase 7.4.1 Discovery

Table 3: Epilepsy Therapeutics, Global, Pharmaceutical Pipeline (Discovery), 2013

Drug name Company Targeted area Mechanism of action

Source: GBI Research, Proprietary Pipeline Products Database [Accessed: November 18, 2013]

7.4.2 Preclinical

Table 4: Epilepsy Therapeutics, Global, Pharmaceutical Pipeline (Preclinical), 2013

Drug/project name Company Targeted area Mechanism of action


Appendix


7.4.3 IND-filed and Phase 0

Table 5: Epilepsy Therapeutics, Global, Pharmaceutical Pipeline (IND/CTA-filed), 2013



7.4.4 Phase I

Table 6: Epilepsy Therapeutics, Global, Pharmaceutical Pipeline (Phase I), 2013

Drug/project name

Company Targeted area Mechanism of action


7.4.5 Phase II

Table 7: Epilepsy Therapeutics, Global, Pharmaceutical Pipeline (Phase II), 2013

Drug/project name

Company Targeted area Mechanism of action


Appendix


7.4.6 Phase III

Table 8: Epilepsy Therapeutics, Global, Pharmaceutical Pipeline (Phase III), 2013



7.4.7 Pre-registration

Table 9: Epilepsy Therapeutics, Global, Pharmaceutical Pipeline (Pre-registration), 2013



Appendix


7.5 Market Forecasting Data Tables to 2019 7.5.1 Major Developed Markets

Table 10: Epilepsy Therapeutics, Major Developed Markets, Market Forecast, 2012–2019

2012 2013 2014 2015 2016 2017 2018 2019 CAGR (%)

Prevalence population (million)

Treatment population (million)

Maximum revenue ($bn)

Projected revenue ($bn)

Minimum revenue ($bn)

Source: GBI Research, Proprietary Marketed Products Database [Accessed: December 14, 2013]

7.5.2 US

Table 11: Epilepsy Therapeutics, US, Market Forecast, 2012–2019

2012 2013 2014 2015 2016 2017 2018 2019 CAGR

(%)



Annual cost of therapy ($)

Maximum revenue ($bn)

Projected revenue ($bn)

Minimum revenue ($bn)


7.5.3 UK

Table 12: Epilepsy Therapeutics, UK, Market Forecast, 2012–2019

2012 2013 2014 2015 2016 2017 2018 2019 CAGR (%)

Prevalence population (‘000)

Treatment population (‘000)


Maximum revenue ($m)

Projected revenue ($m)

Minimum revenue ($m)


Appendix


7.5.4 France

Table 13: Epilepsy Therapeutics, France, Market Forecast, 2012–2019

2012 2013 2014 2015 2016 2017 2018 2019 CAGR (%)








7.5.5 Germany

Table 14: Epilepsy Therapeutics, Germany, Market Forecast, 2012–2019

2012 2013 2014 2015 2016 2017 2018 2019 CAGR (%)








7.5.6 Italy

Table 15: Epilepsy Therapeutics, Italy, Market Forecast, 2012–2019

2012 2013 2014 2015 2016 2017 2018 2019 CAGR (%)








Appendix


7.5.7 Spain

Table 16: Epilepsy Therapeutics, Spain, Market Forecast, 2012–2019

2012 2013 2014 2015 2016 2017 2018 2019 CAGR (%)








7.5.8 Japan

Table 17: Epilepsy Therapeutics, Japan, Market Forecast, 2012–2019

2012 2013 2014 2015 2016 2017 2018 2019 CAGR (%)




Maximum Revenue ($m)

Projected Revenue ($m)

Minimum Revenue ($m)


7.5.9 Canada

Table 18: Epilepsy Therapeutics, Canada, Market Forecast, 2012–2019

2012 2013 2014 2015 2016 2017 2018 2019 CAGR

(%)








Appendix


7.6 Research Methodology GBI Research’s dedicated research and analysis teams consist of experienced professionals with marketing, market research and consulting backgrounds in the pharmaceutical industry as well as advanced statistical expertise.

GBI Research adheres to the codes of practice of the Market Research Society (www.mrs.org.uk) and the Strategic and Competitive Intelligence Professionals (www.scip.org) .

All GBI Research databases are continuously updated and revised.

7.6.1 Coverage The objective of updating GBI Research coverage is to ensure that it represents the most up-to-date vision of the industry possible.

Changes to the industry taxonomy are built on the basis of extensive research of company, association and competitor sources.

Company coverage is based on three key factors: market capitalization, revenues and media attention/innovation/market potential.

An exhaustive search of 56 member exchanges is conducted and companies are prioritized on the basis of their market capitalization.

The estimated revenues of all major companies, including private and governmental, are gathered and used to prioritize coverage.

Companies which is making the news, or which are of particular interest due to their innovative approach, are prioritized.

GBI Research aims to cover all major news events and deals in the pharmaceutical industry, updated on a daily basis.

The coverage is further streamlined and strengthened with additional inputs from GBI Research’s expert panel (see below).

7.6.2 Secondary Research The research process begins with exhaustive secondary research on internal and external sources in order to source qualitative and quantitative information relating to each market.

The secondary research sources that are typically referred to include, but are not limited to:

Company websites, annual reports, financial reports, broker reports, investor presentations and US Securities and Exchanges Commission (SEC) filings

Industry trade journals, scientific journals and other technical literature

Internal and external proprietary databases

Relevant patent and regulatory databases

National government documents, statistical databases and market reports

Procedure registries

News articles, press releases and web-casts specific to the companies operating in the market

7.6.3 Primary Research GBI Research conducts hundreds of primary interviews a year with industry participants and commentators in order to validate its data and analysis. A typical research interview fulfills the following functions:

It provides first-hand information on the market size, market trends, growth trends, competitive landscape and future outlook

It helps in validating and strengthening the secondary research findings

It further develops the analysis team’s expertise and market understanding

Appendix


Primary research involves email and telephone interviews as well as face-to-face interviews for each market, category, segment and sub-segment across geographies

The participants who typically take part in such a process include, but are not limited to:

Industry participants: CEOs, VPs, marketing/product managers, market intelligence managers and national sales managers

Hospital stores, laboratories, pharmacies, distributors and paramedics

Outside experts: Investment bankers, valuation experts, research analysts specializing in specific medical equipment markets

Key opinion leaders: Physicians and surgeons specializing in different therapeutic areas corresponding to different kinds of medical equipment.

7.6.4 Therapeutic Landscape Revenues for each indication, geography-wise, are arrived at by utilizing the GBI Research market forecasting model. The global revenue for each indication is the sum value of revenues of all seven regions.

The annual cost of therapy for each indication is arrived at by considering the cost of the drugs, dosage of the drugs and the duration of the therapy.

The generic share of the market for each indication is obtained by calculating the prescription share for generic drugs and the respective cost of treatment.

The treatment usage pattern which includes quantitative data on the diseased population, treatment-seeking population, diagnosed population and treated population for an indication, is arrived at by referring to various sources as mentioned below.

GBI Research uses the epidemiology-based treatment flow model to forecast market size for therapeutic indications.

7.6.4.1 Epidemiology-based Forecasting

The forecasting model used at GBI Research makes use of epidemiology data gathered from research publications and primary interviews with physicians to represent the treatment flow patterns for individual diseases and therapies. The market for any disease segment is directly proportional to the volume of units sold and the price per unit.

Sales = Volume of Units sold X Price per Unit

The volume of units sold is calculated on the average dosage regimen for that disease, duration of treatment and number of patients who are prescribed drug treatment (prescription population). Prescription population is calculated as the percentage of population diagnosed with a disease (diagnosis population). Diagnosis population is the population diagnosed with a disease expressed as a percentage of the population that is seeking treatment (treatment-seeking population). Prevalence of a disease (diseased population) is the percentage of the total population who suffer from a disease/condition.

Data on the treatment seeking rate, diagnosis rate and prescription rate, if unavailable from research publications, are gathered from interviews with physicians and are used to estimate the patient volumes for the disease under consideration. Therapy uptake and compliance data are fitted in the forecasting model to account for patient switching and compliance behavior.

To account for the differences in patient affordability of drugs across various geographies, macroeconomic data such as inflation and GDP; and healthcare indicators such as healthcare spending, insurance coverage and average income per individual are used.

Annual cost of therapy is calculated using product purchase frequency and the average price of the therapy. Product purchase frequency is calculated from the dosage data available for the therapies and drug prices are gathered from public sources. The sources for the price of drugs are RxUSA, ZenRx and the British National Formulary.

Appendix


The epidemiology-based forecasting model uses a bottom-up methodology and it makes use of estimations in the absence of data from research publications. Such estimations may result in a final market value that is different from the actual value. To correct this ‘gap’ the forecasting model uses ‘triangulation’ with the help of base-year sales data (from company annual reports, internal and external databases) and sales estimations.

Analogous Forecasting Methodology

Analogous forecasting methodology is used to account for the introduction of new products, patent expiries of branded products and the subsequent introduction of generics. Historic data for new product launches and generics penetration are used to arrive at robust forecasts. An increase or decrease of prevalence rates, treatment seeking rate, diagnosis rate and prescription rate are fitted into the forecasting model to estimate the market growth rate.

GBI Research’s proprietary model enables it to account for the impact of individual drivers and restraints in the growth of the market. The year of impact and the extent of impact are quantified in the forecasting model to provide close-to-accurate data sets.

Diseased Population

The diseased population for any indication is the prevalence. The prevalence population for this report is taken from articles published in various journals including the Investigative Ophthalmology & Visual Science, Journal of Ophthalmology and Archives of Ophthalmology.

Prescription Population

Treatment options for AMD depend upon the stage of the disease and the type of lesion. Options for the treatment of AMD include surgical intervention, non-biologic drug therapy and biologic drug therapy. The prescription population is defined as the number of patients who are prescribed biologic drug therapy. This is calculated as a percentage of the diagnosis population. The prescription population proportion is taken from articles published in various journals including the Journal of Ocular Biology, Diseases, Informatics, and Retina.

Appendix


7.6.4.2 Market Size by Geography

The treatment usage pattern and annual cost of therapy in each country has been factored in while deriving the individual country market size.

Forecasting Model for Therapeutic Areas

Figure 25: GBI Research Market Forecasting Model

D is ease P opu la ti onGener al Po pu la tio n 743 ,535 ,048

Q ualifying c ond ition 1 (Age /S ex/O c c upation e tc )Q ualifying c ond ition 2 (Age /S ex/O c c upation e tc )

Preva l ence t i ssu e va lve disease 0 .2% 1 ,784 ,484 Q ualifying c ond ition (c om plic at ion , s eve rity)D IS EA SE D P OPU LA T IO N 1,784 ,484

T r eatm en t Flow P attern sT rea tm ent S eek i ng R at e (Sy m ptom s/ Dis A wareness) 89% 1,588 ,191 Di agn osis Rat e (C lin ica l and D iagn ostic Tes ts ) 75% 1,191 ,143 Prescr iption R ate ( Ph ysic ian P ercep t io n, Tr ea tm ent E ffec tiv e n ess)

Tis s ue V alve 70% 833 ,800 O the r T reatm en ts fo r Va lve (Su r g /M ed/N one) -

F ulfi llm en tA vailab ilit y NAW ill ingness to U s e (Pa tient Pe rc ep tions) NAR eady to U se (S urge ry e lig ib i lity , R eus e e tc ) NA

Affo rd abil it y at PriceH E as % of G D P s pendA verage Inc om e (per ind ividual)P at ien t O u t-of -poc ket Budge t (A nnua l)

Budget a lloc a tion to one-t im e s u rge ryBudget a lloc a tion to o the r h ealth needs

A verage Pay or C overageP at ien t L iab il ityTa rge t Pr ic e ( @20% pa t liab )A SP for C os t o f T herapy

T O TA L P AT IEN T V OLU M E SPro du ct P urch ase Fr equ en c y 1

T OT A L U N IT VO LU MES

Pr ic in g per Un it 18,000$ In f lat ionP rice D ec reas e due to c om pet it ion

M ar ket Va lu e

G B I R esear ch M ar ke t Siz in g M o de l

Source: GBI Research

The figure above represents a typical forecasting model used by GBI Research. As discussed previously, the model is built on treatment flow patterns. The model starts with the general population, then the diseased population as a percentage of the general population, and then follows the treatment seeking population as a percentage of the diseased population and the diagnosed population as a percentage of the treatment seeking population. Finally, the total volume of units sold is calculated by multiplying the treated population by the average dosage per year per patient.

Appendix


7.6.5 Geographical Landscape GBI Research has analyzed four geographical locations in this report: Australia, China, India and Japan. The total market size for each country is provided, which is the sum value of the market sizes of all the indications for that particular country.

Articles from research journals and agency publications such as the Journal of Ophthalmology, Investigative Ophthalmology & Visual Science, National Institute of Health and ClinicalTrials.gov are the sources of data for the estimation of market sizes and making forecasts.

7.6.6 Pipeline Analysis This section provides a list of molecules at various stages in the pipeline for various indications. The list is sourced from an internal database and validated for the accuracy of its phase and mechanism of action data at ClinicalTrials.gov and through company websites. The section also includes a list of promising molecules that is narrowed down based on the results of the clinical trials at various stages and the novelty of mechanism of action. A heat map, sourced from relevant clinical trials, is provided in order to compare these products to one another in addition to currently marketed products. The latest press releases issued by the relevant companies and news reports are also sources of information for the status of the molecule in the pipeline. This list of pipeline molecules, in conjunction with a list of ongoing and completed clinical trials, is analyzed in this section, and a full breakdown of pipeline molecules and clinical trials by phase, molecule type and molecular target is provided.

7.7 Expert Panel Validation GBI Research uses a panel of experts to cross-verify its databases and forecasts.

GBI Research’s expert panel comprises marketing managers, product specialists, and international sales managers from pharmaceutical companies, academics from research universities and key opinion leaders from hospitals.

Historic data and forecasts are relayed to GBI Research’s expert panel for feedback and are adjusted in accordance with their feedback.

7.9 Disclaimer All Rights Reserved.

No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission of the publisher, GBI Research.

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