REFERENCE CODE GDHC239CFR PUBLICAT ION DATE APRIL 2014 NEUROPATHIC PAIN - US DRUG FORECAST AND MARKET ANALYSIS TO 2022
Executive Summary Sales for Neuropathic Pain (NP) in the US The US NP market was valued at an estimated $1.8 billion in 2012. GlobalData expects the market to grow at a Compound Annual Growth Rate (CAGR) of 2.7% to $2.3 billion by 2022. Major drivers of the growth of the NP market over the forecast period include: Figure below illustrates the US NP sales during the forecast period. Sales for Neuropathic Pain in the US by Therapeutic Class, 2012 2022 19% 2012 Total: $1.78bn 0% US healthcare reform will increase patient access to treatment and thus increase treatment rates. US obesity epidemic will lead to the increased prevalence of type 2 diabetes, and consequently, an increased prevalence of 10% 24% 0% 1% 46% Calcium alpha-2- delta ligand anticonvulsants Sodium channelblocking anticonvulsants TCAs PDN. The increasing NP incidence due to the growing elderly population The approval of novel formulations and first-in- 20% 2022 Total: $2.32bn 5% 47% SNRI antidepressants Opioids Topicals class therapies in the pipeline for NP, which will drive sales in this market 8% Other Major barriers to the growth of the NP market over the forecast period include: Launch of generic competitors to Cymbalta sand Lidoderm in 2013, and Lyrica in 2018, will lead to market contraction. 16% Source: GlobalData 0% 4% Medicare spending cuts will create greater emphasis on the affordability of healthcare. Prescription drug abuse, particularly with opioids, is leading to stricter regulations governing their use. 2
Executive Summary What Do Physicians Think? When queried about the most challenging aspects of treating patients with NP, key opinion leaders (KOLs) were in agreement, citing efficacy and safety as the key issues. Well, I think the efficacy and safety of the drugs we have available, because with the given monotherapy, we can have only 50% of the patients [responding]. And many patients also stop treatment due to side effects, especially central nervous system adverse event[s] like dizziness, nausea, somnolence, and concentration difficulties. [EU] KOL, October 2013 If you look at all the clinical trials Lyrica, duloxetine, opioids, Qutenza you name it. So, what is the outcome? Forty percent [of] patients get 30% pain relief. So, what it means is that 60% of patients got no pain relief, and even those who get 30% of pain relief still have plenty of pain. So, if you have a pain [score] of eight, and your pain is down to five, you are still in a lot of pain. So, [when] all [is] said and done, it s pretty pathetic. [US] KOL, September 2013 Another major challenge observed in clinical practice is the underdosing of key medications. These drugs are notoriously underdosed. So, they come in with 600[mg] or 900[mg] gabapentin, or 75mg pregabalin, per day, which have not been shown to be effective in those trials. But, I would not rule out that there are certain patients who are doing well on low doses, which may not be placebo, also. But these are all assumptions, because it has never been demonstrated in clinical trials that 75mg of pregabalin are effective. Even 150mg are not. [EU] KOL, October 2013 If the drug is difficult to titrate, it s usually that they [physicians] start treatment, and then they just...i do not know, they forget titrating. For them, it s much easier to handle drugs which actually you don t have to titrate that much. So, if you look at duloxetine, for example, there you don t have this danger, because they start usually with 30[mg], and then they go to 60[mg], and that s it. But, with gabapentin, especially, and also with pregabalin, you need to titrate for longer periods of time. And maybe that s too cumbersome for them, inconvenient. So, it s much better to have a drug which doesn t need that much of a titration. [EU] KOL, October 2013 Physicians also raised concerns about the lack of guidance on combination therapies, which are frequently necessary in the treatment of NP. 3
Executive Summary So, I guess my concern is that this in the real world, we treat medical illness, including chronic pain, with multi-drug approaches, and then the data that we get typically from studies seeking FDA approval or otherwise is based upon patients who are being compared with placebo in a single therapy, and we don t get guidance about how to take care of people in the real world. And we also don t get the benefit of knowing how these drugs combine together, [how they] work with each other, and I think that s the shame. It is a big obstacle, because you know the providers of care don t have enough studies to support their use of multiple types of medications at one time safe or not safe, what s likely to help, what s not likely to help. [US] KOL, July 2013 Although physicians indicated a need for novel therapies, they also pointed out that there are sometimes financial pressures to prescribe less expensive drugs first, even though they may be poorly tolerated by the patient. There are two drugs that are approved in the United States for the management of peripheral neuropathy: one is duloxetine, and the other one is pregabalin.now if you, in the United States, want to prescribe duloxetine or pregabalin, the thirdparty payer or the insurer will refuse to pay for it. [They say] you should use a simpler drug you should use a drug like [a] tricyclic [antidepressant] first. So, if you use a drug like amitriptyline first, what happens is the patients hate you. You know? They become constipated, they get erectile dysfunction, and they get urinary retention. They get [low] blood pressure, they get a dry mouth they hate you for that. [US] KOL, August 2013 Now, what are we doing in clinical practice, we use a drug like gabapentin [be]cause it is very cheap today. [US] KOL, August 2013 In terms of promising pipeline drugs, Daiichi- Sankyo s DS-5565 was highlighted by physicians as being most promising. The Daiichi Sankyo compound, for example, the calcium [channel] alpha-2-delta [ligand], which of course it s not a new mechanism, but [it] could be that this is something which maybe is more effective than pregabalin, or maybe more safe, theoretically. They will need to prove this.so, I think, among the systemically-administered drugs in the pipelines, I think the Daiichi compound has the best chance. But it s nothing new. Not [a] new mechanism or so. [EU] KOL, October 2013 4
1 1... 5 1.1 List of Tables... 11 1.2 List of Figures... 13 2 Introduction... 14 2.1 Catalyst... 14 2.2 Related Reports... 14 3 Disease Overview... 16 3.1 Clinical Manifestations of Neuropathic Pain Signs and Symptoms... 18 3.1.1 Painful Diabetic Neuropathy... 20 3.1.2 Postherpetic Neuralgia... 21 3.1.3 Trigeminal Neuralgia... 21 3.2 Etiology and Pathophysiology... 22 3.2.1 Etiology... 23 3.2.2 Pathophysiology... 24 4 Disease Management... 32 4.1 Diagnosis and Treatment Overview... 32 4.1.1 Diagnosis... 32 4.1.2 Treatment Overview and Guidelines... 39 4.2 US... 48 4.2.1 Diagnosis and Referral... 48 4.2.2 Drug Treatment... 50 5
5 Competitive Assessment... 54 5.1 Overview... 54 5.2 Tricyclic Antidepressants... 58 5.2.1 Overview... 58 5.2.2 Efficacy... 59 5.2.3 Safety... 60 5.3 Calcium Channel Alpha-2-Delta Ligands (Anticonvulsants)... 61 5.3.1 Overview... 61 5.3.2 Efficacy... 62 5.3.3 Safety... 64 5.3.4 Lyrica... 64 5.4 Sodium Channel-Blocking Anticonvulsants (TN)... 68 5.4.1 Overview... 68 5.4.2 Efficacy... 69 5.4.3 Safety... 69 5.5 Serotonin-Norepinephrine Reuptake Inhibitors (Antidepressants)... 70 5.5.1 Overview... 70 5.5.2 Efficacy... 71 5.5.3 Safety... 71 5.5.4 Cymbalta... 71 5.6 Opioids... 74 5.6.1 Overview... 74 5.6.2 Efficacy... 75 6
5.6.3 Safety... 76 5.6.4 Nucynta ER/Palexia SR... 76 5.7 Topical Therapies... 79 5.7.1 Overview... 79 5.7.2 Efficacy... 80 5.7.3 Safety... 80 5.7.4 Lidoderm/Versatis... 81 5.7.5 Qutenza... 83 6 Unmet Need and Opportunity... 87 6.1 Overview... 87 6.2 Physician Knowledge or Awareness... 88 6.2.1 Unmet Need... 88 6.2.2 Gap Analysis... 89 6.2.3 Opportunity... 90 6.3 Diagnostic Challenges... 90 6.3.1 Unmet Need... 90 6.3.2 Gap Analysis... 91 6.3.3 Opportunity... 91 6.4 Low Treatment Rate and Underdosing of Medications... 91 6.4.1 Unmet Need... 91 6.4.2 Gap Analysis... 93 6.4.3 Opportunity... 93 6.5 Unsatisfactory Efficacy and Safety Profiles of Pharmacological Treatments... 94 7
6.5.1 Unmet Need... 94 6.5.2 Gap Analysis... 94 6.5.3 Opportunity... 95 6.6 Elderly Patient Population Drug Tolerability... 96 6.6.1 Unmet Need... 96 6.6.2 Gap Analysis... 96 6.6.3 Opportunity... 97 6.7 Rational or Personalized Therapies... 97 6.7.1 Unmet Need... 97 6.7.2 Gap Analysis... 98 6.7.3 Opportunity... 98 7 Pipeline Assessment... 100 7.1 Overview... 100 7.2 Promising Drugs in Clinical Development... 101 7.2.1 Eslicarbazepine Acetate... 103 7.2.2 Topical Clonidine Gel... 107 7.2.3 Cebranopadol... 110 7.2.4 DS-5565... 113 7.2.5 CNV-2197944... 117 7.2.6 CNV-1014802... 120 7.2.7 Eladur (bupivacaine patch)... 123 8 Market Outlook... 127 8.1 Drivers and Barriers Global Issues... 127 8
8.1.1 Driver: Aging Population in the 7MM... 127 8.1.2 Driver: Increase in Prevalence and Diagnosis of Type 2 Diabetes Will Grow the PDN Market... 127 8.1.3 Driver: Approval of New NP Drugs... 128 8.1.4 Barrier: NP Market Dominated by Generics... 128 8.1.5 Barrier: Challenges Selecting the Most Relevant Pathophysiological Targets for Drug Development... 128 8.1.6 Barrier: Underserved Trigeminal Neuralgia Indication... 129 8.1.7 Barrier: Competition from Interventional Therapies... 129 8.2 United States... 129 8.2.1 Forecast... 129 8.2.2 Key Events... 140 8.2.3 Drivers and Barriers... 140 9 Appendix... 143 9.1 Bibliography... 143 9.2 Abbreviations... 154 9.3 Methodology... 159 9.4 Forecasting Methodology... 159 9.4.1 Diagnosed PDN, PHN, and TN Patients... 159 9.4.2 Percent Drug-Treated Patients... 160 9.4.3 Drugs Included In Each Therapeutic Class... 160 9.4.4 Launch and Patent Expiry Dates... 160 9.4.5 General Pricing Assumptions... 161 9
9.4.6 Individual Drug Assumptions... 161 9.4.7 Generic Erosion... 165 9.4.8 Pricing of Pipeline Agents... 165 9.5 Physicians and Specialists Included in This Study... 166 9.6 About the Authors... 168 9.6.1 Author... 168 9.6.2 Global Head of Healthcare... 169 9.7 About GlobalData... 170 9.8 Disclaimer... 170 10
1.1 List of Tables Table 1: Classification of NP Syndromes Based on the Site of Somatosensory Damage... 18 Table 2: Signs and Symptoms of NP... 19 Table 3: Screening Tools for NP... 33 Table 4: NP-Related Signs and Symptoms... 35 Table 5: Treatment Guidelines for NP... 40 Table 6: Recommended Drug Therapies for NP Conditions by Line of Therapy... 46 Table 7: Most Prescribed Drugs for NP by Indication and Line of Therapy in the Global Markets, 2012... 48 Table 8: US NP Diagnosis and Referral Metrics... 50 Table 9: US NP Treatment Metrics... 53 Table 10: NNT and NNH for Classes of Oral Drugs used in NP Treatment, 2013... 56 Table 11: Select Products Used for NP Treatment, 2013... 58 Table 12: Product Profile Lyrica... 65 Table 13: Lyrica SWOT Analysis, 2013... 67 Table 14: Product Profile Cymbalta... 72 Table 15: Cymbalta SWOT Analysis, 2013... 74 Table 16: Product Profile Nucynta ER/Palexia SR... 77 Table 17: Nucynta ER/Palexia SR SWOT Analysis, 2013... 78 Table 18: Product Profile Lidoderm/Versatis... 82 Table 19: Lidoderm/Versatis SWOT Analysis, 2013... 83 Table 20: Product Profile Qutenza... 84 Table 21: Qutenza SWOT Analysis, 2013... 86 Table 22: Unmet Need and Opportunity in NP... 88 Table 23: NP Promising Drugs in Clinical Development... 102 11
Table 24: Comparison of Drugs in Development for NP, 2014... 102 Table 25: Product Profile Eslicarbazepine Acetate... 104 Table 26: Phase II: Efficacy of Eslicarbazepine Acetate in PHN... 105 Table 27: Phase II: Efficacy of Eslicarbazepine Acetate in PDN... 105 Table 28: Eslicarbazepine Acetate SWOT Analysis, 2013... 107 Table 29: Product Profile Topical Clonidine Gel... 108 Table 30: Topical Clonidine Gel SWOT Analysis, 2013... 110 Table 31: Product Profile Cebranopadol... 111 Table 32: Cebranopadol SWOT Analysis, 2013... 113 Table 33: Product Profile DS-5565... 115 Table 34: DS-5565 SWOT Analysis, 2013... 117 Table 35: Product Profile CNV-2197944... 118 Table 36: CNV-2197944 SWOT Analysis, 2013... 120 Table 37: Product Profile CNV1014802... 121 Table 38: CNV-1014802 SWOT Analysis, 2013... 123 Table 39: Product Profile Eladur... 124 Table 40: Eladur SWOT Analysis, 2013... 126 Table 41: NP Market Drivers and Barriers, 2012 2022... 127 Table 42: Sales Forecasts ($) for NP in the United States, 2012 2022... 132 Table 43: Sales Forecasts ($) for PDN in the United States, 2012 2022... 134 Table 44: Sales Forecasts ($) for PHN in the United States, 2012 2022... 136 Table 45: Sales Forecasts ($) for TN in the United States, 2012 2022... 138 Table 46: Key Events Impacting Sales for NP in the United States, 2012 2022... 140 Table 47: NP Market Drivers and Barriers in the United States, 2012 2022... 140 12
Table 48: Key Launch Dates... 160 Table 49: Key Patent/Exclusivity Expiries... 161 1.2 List of Figures Figure 1: Nociceptive Versus Neuropathic Pain... 17 Figure 2: Etiology and Pathophysiology of NP... 22 Figure 3: Pain Pathway Somatosensory System... 25 Figure 4: Pathophysiological Mechanisms of NP at Different Levels of the Nervous System... 29 Figure 5: Pathophysiological Targets of NP Drugs... 30 Figure 6: NeuSPIG Diagnostic Certainty Algorithm for NP... 36 Figure 7: General Treatment Algorithm for NP... 45 Figure 8: Competitive Assessment of Mid-to-Late Stage Pipeline Agents in NP, 2012 2022... 103 Figure 9: Sales for NP in the United States by Drug Class, 2012 2022... 133 Figure 10: Sales for PDN in the United States by Drug Class, 2012 2022... 135 Figure 11: Sales for PHN in the United States by Drug Class, 2012 2022... 137 Figure 12: Sales for TN in the United States by Drug Class, 2012 2022... 139 13
Introduction 2 Introduction 2.1 Catalyst The entire neuropathic pain (NP) market is characterized by a high level of unmet need across all indications, and across the seven major markets (7MM) (US, France, Germany, Italy, Spain, UK, and Japan). The market, however, is anticipated to grow during the forecast period, from $2.58 billion in 2012 to $3.53 billion in 2022, at a Compound Annual Growth Rate (CAGR) of 3.19%. During this time, the NP market will be characterized by the following key events, drivers, and barriers: Growth in the global market will be driven by the growing incidence of NP as a result of the increasing elderly population, the increasing prevalence of type 2 diabetes and the resultant rise in painful diabetic neuropathy (PDN) cases, as well as the market entry of seven pipeline drugs (DS-5565, eslicarbazepine, cebranopadol, topical clonidine, Eladur, CNV-2197944, and CNV-1014802). The fastest-growing market will be Japan, which will end the forecast period accounting for 14% of the market, with projected sales of $491m and a CAGR of 6.38%. This higher-thanaverage growth in Japan will be driven by the fact that its population is aging at a faster rate than any of the other countries in the 7MM, as well as by the delayed launches and continued growth of Lyrica (pregabalin) and Cymbalta (duloxetine) in Japan. However, growth in the rest of the 6MM will be greatly impacted by the patent expirations and subsequent generic erosion of the key leading brands, Lyrica, Cymbalta, and Lidoderm (lidocaine patch 5%). 2.2 Related Reports GlobalData (2014). Neuropathic Pain Global Drug Forecast and Market Analysis to 2022, April 2014, GDHC70PIDR GlobalData (2014). Neuropathic Pain 5EU Drug Forecast and Market Analysis to 2022, April 2014, GDHC240CFR GlobalData (2014). Neuropathic Pain Japan Drug Forecast and Market Analysis to 2022, April 2014, GDHC241CFR 14
Introduction GlobalData (2014). Lyrica (Neuropathic Pain) - Forecast and Market Analysis to 2022, April 2014, GDHC405DFR GlobalData (2014). Cymbalta (Neuropathic Pain) - Forecast and Market Analysis to 2022, April 2014, GDHC406DFR GlobalData (2014). Nucynta ER/Palexia SR (Neuropathic Pain) - Forecast and Market Analysis to 2022, April 2014, GDHC407DFR GlobalData (2014). Lidoderm/Versatis (Neuropathic Pain) - Forecast and Market Analysis to 2022, April 2014, GDHC408DFR GlobalData (2014). Qutenza (Neuropathic Pain) - Forecast and Market Analysis to 2022, April 2014, GDHC409DFR GlobalData (2014). Eslicarbazepine acetate (Neuropathic Pain) - Forecast and Market Analysis to 2022, April 2014, GDHC410DFR GlobalData (2014). DS5565 (Neuropathic Pain) - Forecast and Market Analysis to 2022, April 2014, GDHC411DFR GlobalData (2014). Eladur (Neuropathic Pain) - Forecast and Market Analysis to 2022, April 2014, GDHC412DFR GlobalData (2014). Topical clonidine (Neuropathic Pain) - Forecast and Market Analysis to 2022, April 2014, GDHC413DFR GlobalData (2014). Cebranopadol (Neuropathic Pain) - Forecast and Market Analysis to 2022, April 2014, GDHC414DFR GlobalData (2014). CNV-2197944 (Neuropathic Pain) - Forecast and Market Analysis to 2022, April 2014, GDHC415DFR GlobalData (2014). CNV-1014802 (Neuropathic Pain) - Forecast and Market Analysis to 2022, April 2014, GDHC416DFR GlobalData (2014). Neuropathic Pain - Current and Future Players, April 2014, GDHC1034FPR 15
Appendix 9.7 About GlobalData GlobalData is a leading global provider of business intelligence in the healthcare industry. GlobalData provides its clients with up-to-date information and analysis on the latest developments in drug research, disease analysis, and clinical research and development. Our integrated business intelligence solutions include a range of interactive online databases, analytical tools, reports, and forecasts. Our analysis is supported by a 24/7 client support and analyst team. GlobalData has offices in New York, San Francisco, Boston, London, India, Korea, Japan, Singapore, and Australia. 9.8 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, GlobalData. 170