nonalcoholic steatohepatitis (nash) - opportunity analysis ... · event-driven update reference...

NONALCOHOLIC STEATOHEPATITIS (NASH) - OPPORTUNITY ANALYSIS AND FORECASTS TO 2017 -

EVENT-DRIVEN UPDATE

REFERENCE CODE GDHC034POA | PUBLICAT ION DATE MARCH 2014

Nonalcoholic Steatohepatitis (NASH) – Opportunity Analysis and Forecasts to 2017 - Event-Driven Update 2 © GlobalData. This report is a licensed product and is not to be copied, reproduced, shared or resold in any form.

NONALCOHOLIC STEATOHEPATITIS (NASH) – OPPORTUNITY ANALYSIS AND FORECASTS TO 2017

- EVENT-DRIVEN UPDATE

Executive Summary

NASH: Key Metrics in Six Major Pharmaceutical Markets

2012 Epidemiology

Prevalent Population – 6MM 59.3m

2012 Market Sales

US $208.4m

5EU $24.5m

Total $232.9m

Pipeline Assessment

Number of drugs in Phase IIb 4

Number of first-in-class drugs 4

Most Promising Pipeline Drugs 2017 Sales

GFT505 (Genfit) $581.8m

Obeticholic acid (OCA) (Intercept Pharmaceuticals/Dainippon Sumitomo Pharma [DSP])

$706.3m

Key Events (2012–2017) Level of Impact

GFT505 Launch in the US, 5EU in Q4 2017

↑↑↑

OCA Launch in the US in Q4 2017 ↑↑↑

2017 Market Sales

US $1.28bn

5EU $77.0m

Total $1.36bn Source: GlobalData. 5EU = France, Germany, Italy, Spain, UK; 6MM = US, 5EU.

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.




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

89%

2%4%2%

2%1%

US

France

Germany

Italy

Spain

UK

2012 Total Sales:$232.9m

94%

1%1%

2%1%

1%

2017 Total Sales:$1,356.1m

Source: GlobalData.

Emerging Market Players Employing Strategies to Improve Diagnostics and Trial Designs

The NASH market is virtually vacant aside from off-

label 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.

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 cost-

effective and touts a desirable efficacy and safety

profile.




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 gold-

standard 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.




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

Vitamin E

Pioglitazone (Actos)

SimtuzumabGFT505 & OCA

Liraglutide

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

0 1 2 3 4 5

Com

mer

cial

Sco

re

Clinical Score Source: GlobalData.

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].”


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:




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.”

[US] key opinion leader, June 2013

“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...”


“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!”





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




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




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




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




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




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




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




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.

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 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. 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).

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




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.

Nonalcoholic Steatohepatitis (NASH) – Opportunity Analysis and Forecasts to 2017- Event-Driven Update 117 © GlobalData. This report is a licensed product and is not to be copied, reproduced, shared or resold in any form.



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.

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