REFERENCE CODE GDHC034POA PUBLICAT ION DATE MARCH 2014 NONALCOHOLIC STEATOHEPATITIS (NASH) - - EVENT-DRIVEN UPDATE
Executive Summary NASH: Key Metrics in Six Major Pharmaceutical Markets 2012 Epidemiology Prevalent Population 6MM 59.3m 2012 Market Sales US 5EU Total Pipeline Assessment $208.4m $24.5m $232.9m Number of drugs in Phase IIb 4 Number of first-in-class drugs 4 Most Promising Pipeline Drugs GFT505 (Genfit) Obeticholic acid (OCA) (Intercept Pharmaceuticals/Dainippon Sumitomo Pharma [DSP]) Key Events (2012 2017) GFT505 Launch in the US, 5EU in Q4 2017 OCA Launch in the US in Q4 2017 2017 Market Sales US 5EU Total Source: GlobalData. 5EU = France, Germany, Italy, Spain, UK; 6MM = US, 5EU. 2017 Sales $581.8m $706.3m Level of Impact $1.28bn $77.0m $1.36bn End of Forecast Surge in Sales for NASH from 2012 2017 GlobalData estimates the 2012 off-label sales for nonalcoholic steatohepatitis (NASH) to be approximately $233m across the US and five major European markets of France, Germany, Italy, Spain, and the UK. By forecast end in 2017, GlobalData expects sales to grow to about $1.36bn, with a compound annual growth rate (CAGR) of 42.2% across the 6MM. We expect the US to claim the most sales, contributing $1.28bn of global sales and a CAGR of 43.8%. Major drivers of growth in the NASH market are attributed to two factors: The growing rate of obesity and diabetes globally. The launch of Genfit s GFT505 and Intercept/DSP s obeticholic acid (OCA) in 2017. In OCA s favor, its Phase II/IIb trial was stopped early in January 2014, after a planned interim analysis showed that the primary endpoint of the study had been met. While for GFT505, Genfit is aligning itself to register GFT505 among the first approved therapies for NASH and the company received Fast Track designation for the GFT505 NASH program on February 14, 2014. We expect the US growth will be due in part to the launch of both of these products, while growth in the 5EU will be predominantly driven by GFT505 during the forecast period. 2
Executive Summary Major barriers to the growth of the NASH market are attributed to: Slow development of therapies specific for NASH. Unclear understanding of the pathophysiology of NASH. Inefficient diagnostic tools for NASH that may lead to delayed diagnosis of NASH. Sales for NASH by Region, 2012 2017 2012 Total Sales: $232.9m 2% 1% 2% 4%2% Emerging Market Players Employing Strategies to Improve Diagnostics and Trial Designs The NASH market is virtually vacant aside from offlabel therapies that do not provide a one size fits all approach. The potential for market leaders to emerge is wide open to all contenders. We expect Gilead and Novo Nordisk to gain market entry after the end of the forecast period in 2017; however, with their market knowledge, their products simtuzumab and liraglutide should do well commercially. As for newcomers Genfit and Intercept/DSP, fame will be claimed since their products will likely launch at the end of the forecast in Q4 2017, thus giving them an early foothold in the NASH market space. 2% 1% 1% 1% 1% 89% 2017 Total Sales: $1,356.1m US France Germany Italy Spain UK Since there is no cure or one specific therapy currently available for NASH, R&D strategies in this market space are complicated. Complications range from unraveling the pathophysiology of NASH, to designing diagnostic tools for more accurate diagnosis and staging, to the design of clinical trials. As our expert leaders have agreed, NASH needs an approved therapy that is costeffective and touts a desirable efficacy and safety profile. Source: GlobalData. 94% 3
Executive Summary Vast Unmet Needs in the NASH Market The level of unmet needs for NASH, including both environmental and clinical, is high and includes patient awareness, physician education, and approved therapies specific to NASH. These issues compound the reasons why the NASH market space is very sparse. A series of unknowns exist for the disease, due to its heterogeneous nature, and its slow progression poses problems for drug development. Vitamin E, the current goldstandard therapy, dominates what little drug therapy NASH market there is. We expect both Genfit s small molecule GFT505 and Intercept Pharmaceuticals/DSP s small molecule OCA to claim patient share in all subpopulations of NASH. These products will likely solve the top unmet need the dire need for an approved therapy for NASH. Opportunities Will Remain for Tools that Provide Accurate Diagnosis There is a major opportunity for new entrants to design better biomarkers than the current liver enzymes: alanine aminotransferase (ALT) and aspartate aminotransferase (AST) as non-invasive surrogates for Nonalcoholic Fatty Liver Disease (NAFLD). Testing may also include cytokeratin-18 (CK18), which may provide clues to hepatocyte cell death. In addition, markers that can assess liver stages are needed, since CK18 is also elevated in other liver conditions. Currently, NASH patients may be diagnosed by chance during routine serological examination, or via invasive liver biopsy. Most NASH patients will be in the mid/late stage of the disease once diagnosed. A more accurate diagnostic tool for determining the extent of fibrosis in NASH patients will also be paramount. That said, we expect these opportunities to remain unmet during the five-year forecast period from 2012 2017. 2017 Launches of Novel Pipeline Products Will Forever Change the Future NASH Treatment Landscape Twelve molecules of interest across all stages of development make up the pipeline for NASH. However, GlobalData believes there are four therapies with the potential to revolutionize the treatment paradigm for NASH in the near term. These four novel, potential first-in-class therapies, which are antifibrotic and antidiabetic by therapeutic class, will target subpopulations (obese, diabetic, and other or healthy donors) within NASH. The four most promising NASH pipeline products are: Genfit s GFT505: anticipated to launch in Q4 2017 across the 6MM. Intercept Pharmaceuticals / Dainippon Sumitomo Pharma s obeticholic acid (INT- 747/DSP-1747): anticipated to launch in Q4 2017 in the US, with an expected launch in the EU after the forecast period of 2012 2017. 4
Executive Summary Gilead s simtuzumab: anticipated to launch after the forecast period of 2012 2017. Novo Nordisk s liraglutide (Victoza): the marketed type 2 diabetes brand is anticipated to launch (with NASH as a new indication) after the forecast period of 2012 2017. Below figure provides a competitive assessment of the most promising NASH pipeline products. Competitive Assessment of Mid-Stage Pipeline Agents in NASH, 2012 2017 Commercial Score 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 Simtuzumab Vitamin E Pioglitazone (Actos) Liraglutide GFT505 & OCA 0.0 0 1 2 3 4 5 Source: GlobalData. Clinical Score What Do the Physicians Think? In regards to comparing profiles on Galmed s Aramchol (an early-stage pipeline product for NASH), GFT505, and OCA, an EU KOL interviewed by GlobalData responded with: these three drugs attack the problem through three different ways that is good because there are more chances at least one of them may work. Also, operating through different pathways, sometime in the future [they] may get combined [to allow for combination treatment]. [EU] key opinion leader, June 2013 GlobalData believes that Novo Nordisk s liraglutide (Victoza) is a pipeline drug worth tracking since it has demonstrated a good preliminary safety and efficacy profile. While discussing the NASH pipeline, a KOL from the EU confirmed our analysis of the product and conveyed excitement over the product. The GLP-1 analogues liraglutide [Novo Nordisk s Victoza] [is the pipeline drug that I am excited about]. [EU] key opinion leader, June 2013 While discussing the pipeline products, one KOL explained why they did not think the Fatty- Acid/Bile-Acid Conjugates (FABACs) inhibitors such as Aramchol were going to succeed: 5
Executive Summary I don t think they [Fatty-Acid/Bile-Acid Conjugates inhibitors] are going to be extremely effective. Several have been tried with modest effects. It is unlikely this is going to be the best game-changer. A number of bile acids have been tested in NASH and they have had modest effect. [US] key opinion leader, June 2013 Other KOLs discussed the types of R&D strategies that should be employed by pharmaceutical companies, and explained what may work and what has failed and thus should be avoided: to reduce apoptosis and hepatic inflammation [is an important strategy] [as well as a drug that is] shown to be safe and reduce liver enzymes. Drugs that reduce insulin resistance or glucose levels are being tested by pharmaceutical companies for this. Companies which are looking to reduce liver fat have not had any impressive effect that I think are truly going to make it. The greatest thing would be to find a NASH drug and an antifibrotic drug that would be combined. Combination therapy in patients who need it... [EU] key opinion leader, June 2013 There is a huge trial going on for an anti-loxl2 monoclonal antibody [Gilead s simtuzumab]. It is an antifibrotic drug, but it s developed mainly for NASH it acts by blocking fibrosis... If it does well in NASH [referring to the positive results it had during primary sclerosing cholangitis trials], then it will change the world! [EU] key opinion leader, June 2013 [US] key opinion leader, June 2013 6
Table of Contents 1 Table of Contents 1 Table of Contents... 7 1.1 List of Tables... 11 1.2 List of Figures... 13 2 Introduction... 14 2.1 Catalyst... 14 2.2 Related Reports... 15 3 Disease Overview... 16 3.1 Etiology and Pathophysiology... 16 3.1.1 Etiology... 16 3.1.2 Pathophysiology... 17 3.2 Symptoms... 20 4 Epidemiology... 21 4.1 Disease Background... 21 4.2 Risk Factors and Comorbidities... 22 4.2.1 Increased age is associated with a worsened disease progression, prognosis, and mortality... 22 4.2.2 Being a male is an independent risk factor in morbidly obese NASH cases... 23 4.2.3 Metabolic conditions, such as type 2 diabetes, considerably increase the risk of NASH. 24 4.3 Global Trends... 25 4.3.1 US... 26 4.3.2 5EU... 27 4.4 Forecast Methodology... 29 7
Table of Contents 4.4.1 Sources Used... 30 4.4.2 Forecast Assumptions and Methods... 32 4.4.3 Sources Not Used... 35 4.5 Epidemiology Forecast of NASH (2012 2022)... 36 4.5.1 Total Prevalent Cases of NASH... 36 4.5.2 Age-Specific Prevalent Cases of NASH... 38 4.5.3 Sex-Specific Prevalent Cases of NASH... 39 4.5.4 Age-Standardized Prevalence of NASH... 41 4.6 Discussion... 41 4.6.1 Conclusions on Epidemiological Trends... 41 4.6.2 Limitations of the Analysis... 42 4.6.3 Strengths of the Analysis... 43 5 Current Treatment Options... 44 5.1 Overview... 44 5.2 Product Profiles Major Off-Label Brands... 46 5.2.1 Vitamin E (numerous generics)... 46 5.2.2 Pioglitazone (Actos)... 50 6 Unmet Needs Assessment and Opportunity Analysis... 54 6.1 Overview... 54 6.2 Unmet Needs Analysis... 55 6.2.1 Lack of Approved Therapies... 55 6.2.2 Identification of Biomarkers for Early Diagnosis and Endpoints... 56 6.2.3 Physician Awareness Due to Understanding of Pathophysiology... 56 8
Table of Contents 6.3 Opportunity Analysis... 57 6.3.1 Therapies with Targeted MOA to NASH... 57 6.3.2 Better Models to Understand Drug Efficacy... 57 6.3.3 Future Tool to Measure Fibrosis in NASH Patients... 57 7 R&D Strategies... 58 7.1 Overview... 58 7.1.1 Understanding Multiple Factors of NASH... 58 7.1.2 Potential for a Personalized Approach... 58 7.2 Clinical Trial Design... 59 7.2.1 Differences in Diagnosis, Monitoring, and Sensitive Imaging Techniques Are Needed... 60 7.2.2 Patient Recruitment Issues... 60 7.2.3 Appropriate Endpoints... 61 7.2.4 Clinical Regulatory Guidelines... 62 8 Pipeline Assessment... 64 8.1 Overview... 64 8.2 Promising Drugs in Clinical Development... 65 8.2.1 GFT505... 65 8.2.2 Obeticholic Acid (INT-747)... 69 8.2.3 Simtuzumab (Formerly GS-6624)... 74 8.2.4 Liraglutide (Victoza)... 77 8.3 Innovative Early-Stage Approaches... 81 8.3.1 Targeting Cytokines... 83 9 Pipeline Valuation Analysis... 85 9
Table of Contents 9.1 Clinical Benchmark of Key Pipeline Drugs... 85 9.2 Commercial Benchmark of Key Pipeline Drugs... 88 9.3 Competitive Assessment... 90 9.4 Top-Line Five-Year Forecast... 90 9.4.1 US... 94 9.4.2 5EU... 95 10 Appendix... 97 10.1 Bibliography... 97 10.2 Abbreviations... 106 10.3 Methodology... 109 10.4 Forecasting Methodology... 109 10.4.1 Diagnosed NASH Patients... 109 10.4.2 Percent Drug-Treated Patients... 110 10.4.3 Drugs Included in Each Therapeutic Class... 110 10.4.4 Launch Dates... 111 10.4.5 General Pricing Assumptions... 111 10.4.6 Individual Off-Label Drug Assumptions... 112 10.4.7 Pricing of Pipeline Agents... 112 10.5 Physicians and Specialists Included in this Study... 113 10.6 About the Authors... 114 10.6.1 Author... 114 10.6.2 Epidemiologist... 115 10.6.3 Global Head of Healthcare... 115 10
Table of Contents 10.7 About GlobalData... 117 10.8 Disclaimer... 117 1.1 List of Tables Table 1: Symptoms of NASH... 20 Table 2: Risk Factors and Comorbidities for NASH... 22 Table 3: Reported Prevalence of NASH in the US and 5EU... 26 Table 4: Reported Prevalence of NAFLD in the US and 5EU... 26 Table 5: 6MM, Sources of Prevalence Data Used in the NASH Epidemiological Forecast... 30 Table 6: 6MM, Prevalent Cases of NASH, Ages 20 Years, Men and Women, N, Selected Years, 2012 2022... 37 Table 7: 6MM, Prevalent Cases of NASH, By Age*, Men and Women, N (Row %), 2012... 38 Table 8: 6MM, Prevalent Cases of NASH, Ages 20 Years, By Sex, N (Row %), 2012... 40 Table 9: Off-Label Treatments for NASH... 46 Table 10: Product Profile Vitamin E... 47 Table 11: Vitamin E SWOT Analysis in NASH, 2013... 49 Table 12: Product Profile Pioglitazone... 51 Table 13: Pioglitazone SWOT Analysis in NASH, 2013... 53 Table 14: Overall Unmet Needs in NASH Current Level of Attainment... 55 Table 15: Current Clinical Trial Design of Key Pipeline Drugs for NASH, 2013... 63 Table 16: NASH Mid-Late-Stage Pipeline, 2013... 65 Table 17: Product Profile GFT505... 67 Table 18: GFT505 SWOT Analysis, 2013... 69 Table 19: Product Profile Obeticholic Acid (INT-747)... 71 Table 20: Obeticholic Acid (INT-747) SWOT Analysis, 2013... 73 11
Table of Contents Table 21: Product Profile Simtuzumab... 75 Table 22: Simtuzumab SWOT Analysis, 2013... 77 Table 23: Product Profile Liraglutide... 78 Table 24: Liraglutide Safety Profile from the LEAD Program... 80 Table 25: Liraglutide SWOT Analysis, 2013... 81 Table 26: Early-Stage Pipeline Products in NASH, 2013... 82 Table 27: Clinical Benchmark of Key Pipeline Drugs for NASH, 2013... 87 Table 28: Commercial Benchmark of Key Pipeline Drugs for NASH, 2013... 89 Table 29: Top-Line Sales Forecasts ($m) for NASH, 2012 2017... 91 Table 30: Key Events Impacting Sales for NASH, 2017... 93 Table 31: NASH Market: US and 5EU Drivers and Barriers, 2012 2017... 93 Table 32: Key Launch Dates... 111 12
Table of Contents 1.2 List of Figures Figure 1: Two-Hit and Multiple-Hits Theories in NASH... 18 Figure 2: Distinct-Hit Pathogenesis in NASH... 19 Figure 3: Stages of Liver Disease... 20 Figure 4: 5EU, Prevalence of NAFLD and Obesity, Ages 20 Years, Men and Women, %... 28 Figure 5: 6MM, Prevalent Cases of NASH, Ages 20 Years, Men and Women, N, Selected Years, 2012 2022... 37 Figure 6: 6MM, Prevalent Cases of NASH, By Age*, Men and Women, N, 2012... 39 Figure 7: 6MM, Prevalent Cases of NASH, Ages 20 Years, By Sex, N, 2012... 40 Figure 8: Liver Biopsy to Confirm NASH... 45 Figure 9: Competitive Assessment of Mid-Stage Pipeline Agents in NASH, 2012 2017... 90 Figure 10: Global Sales for NASH by Region, 2012 2017... 92 13
Introduction 2 Introduction 2.1 Catalyst Currently, the NASH market is very dynamic, with growing interest in the therapeutic area showcased by these recent market events: Intercept Pharmaceuticals announced that the Phase II/IIb FLINT trial of its pipeline candidate OCA had been stopped early, after a planned interim analysis showed that the primary endpoint of the study had been met. The January 9, 2014 announcement led to a surge in the company s share price. On January 10, 2014 Genfit presented further information on the clinical program of its Phase IIb pipeline candidate GFT505. This presentation highlighted that Genfit is aligning itself to register GFT505 among the first approved therapies for NASH. The NASH market is extremely sparse, and off-label therapies such as vitamin E and pioglitazone (Takeda s Actos) make up the treatment paradigm. The lack of efficacious therapies specific for treating NASH will allow several pipeline products to emerge uncontested On February 14, 2014, Genfit announced that the US FDA had granted Fast Track designation to the GFT505 NASH program. GlobalData s assessment of the NASH market revealed that it is extremely sparse, and offlabel therapies such as vitamin E and pioglitazone (Takeda s Actos) make up the treatment paradigm. The lack of efficacious therapies specific for treating NASH will allow several pipeline products to emerge uncontested. This report analyzes the four most advanced pipeline products, two of which we estimate will launch at the end of the forecast period in 2017. The four products are: Genfit s peroxisome proliferator-activated receptor alpha, delta (PPARa,d) agonist, GFT505. Anticipated to launch in Q4 2017 in the US and 5EU. Intercept Pharmaceuticals/Dainippon Sumitomo Pharma s farnesoid X receptor (FXR), obeticholic acid (INT-747/DSP-1747). Anticipated to launch in Q4 2017 in the US. We expect launch in the EU after the forecast period of 2012 2017. Gilead s lysyl oxidase-like 2 (LOXL2) inhibitor, simtuzumab. Novo Nordisk s glucagon-like peptide-1 (GLP-1), liraglutide (Victoza). 14
Introduction As mentioned, GFT505 and OCA will be virtually uncontested once they enter the market. We expect each therapy to gain patient share from the three subpopulations (obese, diabetic, and other [defined as healthy donors]) within NASH. Regardless of the novelty each new therapy brings to the paradigm, their presence will be welcomed with open arms within the NASH community. 2.2 Related Reports GlobalData (2013). Type 2 Diabetes Global Drug Forecast and Market Analysis to 2022, July 2013, GDHC54PIDR. GlobalData (2013). Obesity Global Drug Forecast and Market Analysis to 2022, October 2013, GDHC50PIDR. 15
Appendix 10.7 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, Boston, London, India and Singapore. 10.8 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. Nonalcoholic Steatohepatitis (NASH) Opportunity Analysis and Forecasts to 2017- Event-Driven Update 117