Stakeholder Opinions: Restless Legs Syndrome - Novel drugs to prosper as lifecycle management strategies fail

ABOUT DATAMONITOR HEALTHCARE 2

About the CNS pharmaceutical analysis team 2

CHAPTER 1 EXECUTIVE SUMMARY 3

Scope of analysis 3

Datamonitor insight into the restless legs syndrome market 4

Contributing experts 6

Related reports 6

Upcoming reports 6

CHAPTER 2 DISEASE OVERVIEW 8

Definition of restless legs syndrome 9

Features and symptoms of restless legs syndrome 9

Primary features of restless legs syndrome: 9

Associated features of restless legs syndrome: 10

Segmentation of restless legs syndrome 10

Severity of restless legs syndrome 10

International Restless Legs Syndrome Study Group Rating Scale (IRLS) 10

Co-morbidities 12

Etiology of restless legs syndrome 12

Primary and secondary restless legs syndrome 12

Idiopathic restless legs syndrome is the most prevalent form of the disease 12

Causes of restless legs syndrome 13

Restless legs syndrome could result from dopaminergic dysfunction and iron deficiency 13

Prevalence of restless legs syndrome 14

15.5 million medically significant restless legs syndrome patients across the seven major markets 14

Datamonitor's methodology of prevalence rate estimates 15

Medically significant restless legs syndrome accounts for around 30% of the restless legs syndrome population 18

Prevalence of restless legs syndrome is higher in the US and 5EU than in Japan 20

Restless legs syndrome is higher in women and increases with age 21

Presentation and diagnosis of restless legs syndrome 22

Disparity between US and 5EU markets points to significant differences between presentation, diagnosis and treatment rates 22

Presentation of restless legs syndrome 24

Around 60% of patients with restless legs syndrome present to a physician 24

Diagnosis 24

Less than 25% of patients who reported consulting a physician for their symptoms received a diagnosis of restless legs syndrome 24

Underdiagnosis is primarily due to a lack of syndrome awareness 25

Patients are often referred to a neurologist for an accurate diagnosis 25

To receive a diagnosis patients must meet all four primary features of restless legs syndrome 26

Laboratory tests can support the correct diagnosis of restless legs syndrome 26

Treatment guidelines for restless legs syndrome 27

Restless legs syndrome treatment algorithm 27

Physical and behavioral treatment 29

Pharmacological management of restless legs syndrome 29

Dopamine agonists are the first-line choice 30

Levodopa use is limited by the risk of augmentation 31

Anticonvulsants are typically used in treatment-resistant restless legs syndrome 32

Opioids can be useful for treatment-resistant, painful restless legs syndrome 33

Hypnotics may alleviate sleep disturbance 34

Iron infusion poses a potential risk to restless legs syndrome revenues 35

CHAPTER 3 UNMET NEEDS 36

Overview of the key unmet needs 37

Key unmet needs description 38

Greater efficacy without augmentation 38

Long-term efficacy remains an unproven entity even for approved therapies 38

Augmentation with dopaminergic treatments represent a significant issue 38

Faster onset of action 39

Patients with occasional daytime symptoms would benefit greatly from a more rapid onset of action 39

Longer duration of action 40

Extended release and patch formulations represent potential to provide continuous low-dose treatment 40

Improved side-effect profile 41

Products with an improved side-effect profile will open up the mild restless legs syndrome market 41

Effective second-line treatment 42

Clinical evidence will promote the availability of dopamine agonist alternatives 42

No or shorter titration 43

A shorter titration would represent a minor advantage over current treatments 43

CHAPTER 4 CURRENT MARKET DYNAMICS 44

Market overview 45

Significant growth of the restless legs syndrome market led by dopamine agonist treatments 45

Requip and Mirapex: the two leading restless legs syndrome brands 47

US market accounts for 90% of restless legs syndrome sales revenue across the seven major markets 48

The low 5EU market value compared to the US is likely due to a greater awareness of the disease in the US 49

The Japanese market may suffer from the lack of recognition of the disease and the lack of legitimacy of dopamine agonists for restless legs syndrome 50

Disparity of current therapies across regions 51

Current therapies 52

Requip 53

Drug overview 53

Brand dynamics 55

Clinical trial data 58

Datamonitor comment 59

Mirapex 64

Drug overview 64

Brand dynamics 66

Clinical trial data 68

Datamonitor comment 68

Qualaquin (Quinine) 69

Drug overview 69

Brand dynamics 71

Datamonitor comment 72

Neurontin (gabapentin) 72

Drug overview 72

Brand dynamics 74

Datamonitor comment 76

CHAPTER 5 PIPELINE ANALYSIS 78

Restless legs syndrome pipeline overview in 2008 79

Pre-registration pipeline drugs 80

Neupro and Solzira, the next two leading brands in the restless legs syndrome market 80

Neupro (rotigotine patch) 81

Drug overview 81

Clinical trial data 82

Datamonitor comment 86

Nenad (lisuride transdermal patch) 87

Drug overview 87

Clinical trial data 89

Datamonitor comment 91

Solzira (gabapentin enacarbil) 91

Drug overview 91

Clinical trial data 93

Datamonitor comment 97

Other pipeline drugs of note 98

Aplindore 98

Clinical trial data 98

Datamonitor comments 99

Lyrica (pregabalin) 100

Ongoing clinical trial 101

Datamonitor comment 101

Ropinirole transdermal gel JZP-7 101

Datamonitor comments 102

Rotigotine nasal spray 102

Clinical trial data 103

Datamonitor comments 103

Recently discontinued pipeline drugs 104

Safinamide 104

BIBLIOGRAPHY 105

Journals 105

Websites 110

Annual reports 117

Datamonitor reports 118

APPENDIX 119

Data definitions, limitations and assumptions 119

Standard units 119

Japanese market data 119

About Datamonitor 119

About Datamonitor Healthcare 120

About the Central Nervous System analysis team 121

Disclaimer 122

List of Tables

Table 1: The International Restless Legs Syndrome Study Group rating scale 11

Table 2: Prevalence of restless legs syndrome (RLS) in the US, Japan and 5EU, 2008 14

Table 3: Datamonitor's estimation of restless legs syndrome (RLS) prevalence rates across the seven major markets, 2008 16

Table 4: Prevalence of restless legs syndrome (RLS) symptoms at any frequency across studies 18

Table 5: Prevalence of medically significant restless legs syndrome (RLS) across studies 19

Table 6: Disparity between US and 5EU restless legs syndrome market values and volumes 22

Table 7: Disparity between US and 5EU restless legs syndrome (RLS) population sizes 23

Table 8: Restless legs syndrome (RLS)-specific sales ($000s) of the current prescribed therapies across the seven major markets, 2004-07 53

Table 9: Requip - Drug profile, 2008 55

Table 10: Mirapex - Drug profile, 2008 65

Table 11: Qualaquin - Drug profile, 2008 70

Table 12: Neurontin - Drug profile, 2008 74

Table 13: Pipeline drugs for restless legs syndrome (RLS), 2008 79

Table 14: Efficacy of the pre-registration drugs assessed by comparing decrease in IRLS scores 80

Table 15: Clinical trial summary for Neupro (rotigotine patch) in restless legs syndrome (RLS), 2008 83

Table 16: Clinical trial summary for Nenad (lisuride transdermal patch) in restless legs syndrome (RLS), 2008 89

Table 17: Clinical trial summary for Solzira (gabapentin enacarbil) in restless legs syndrome (RLS), 2008 94

Table 18: Periodic limb movement index (PLMI) during sleep 99

List of Figures

Figure 1: Estimated projection of the proportion of individuals with restless legs syndrome (RLS) classified as having a medically significant diagnosis, 2008-2045 20

Figure 2: Prevalence rates (%) and number of restless legs syndrome (RLS) sufferers in the 5EU by age group, 2008 21

Figure 3: Datamonitor's assessment of the difference between the US and 5EU restless legs syndrome (RLS) market values 23

Figure 4: Datamonitor's restless legs syndrome (RLS) treatment algorithm, 2008 28

Figure 5: Key unmet needs in restless legs syndrome (RLS) treatment, 2008 37

Figure 6: Restless legs syndrome (RLS)-specific sales ($m) by class across the seven major markets, 2004-07 45

Figure 7: Restless legs syndrome (RLS)-specific sales volume (IMS standard units) by class across the seven major markets, 2004-07 46

Figure 8: Restless legs syndrome (RLS)-specific sales value ($m) by leading brands across the seven major markets, 2007 47

Figure 9: Restless legs syndrome (RLS)-specific sales revenue ($m) in the US, Japan and 5EU, 2007 48

Figure 10: Restless legs syndrome (RLS) market value ($m) share by product, across the US, 5EU and Japan, 2007 51

Figure 11: Requip (ropinirole) restless legs syndrome (RLS)-specific sales ($000s) across the seven major markets, 2004-07 56

Figure 12: Requip (ropinirole) restless legs syndrome (RLS)-specific sales ($m) distribution across the seven major markets, 2007 57

Figure 13: Datamonitor's assessment of GlaxoSmithKline's strategy in restless legs syndrome, 2008 59

Figure 14: Datamonitor's assessment of GlaxoSmithKline's development of two different extended-release formulations of Requip for restless legs syndrome and Parkinson's disease 61

Figure 15: Datamonitor's conceptual representation of the pharmacokinetic profiles for Requip IR and Requip XL in restless legs syndrome patients 62

Figure 16: Mirapex (pramipexole) restless legs syndrome-specific sales ($000s) across the seven major markets, 2004-07 66

Figure 17: Mirapex (pramipexole) restless legs syndrome (RLS)-specific sales ($m) distribution across the seven major markets, 2007 67

Figure 18: Qualaquin (quinine) restless legs syndrome (RLS)-specific sales ($000s) across the seven major markets, 2004-07 71

Figure 19: Neurontin (gabapentin) restless legs syndrome (RLS)-specific sales ($000s) across the seven major markets, 2004-07 75

Figure 20: Neurontin (gabapentin) restless legs syndrome-specific sales distribution across the seven major markets ($m), 2007 76

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