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Hepatitis C - Small-Molecule Antivirals Pave the Way for Triple Therapy

Posted on: Wednesday, 20 February 2008, 05:24 CST

Reportlinker.com announces that a new market research report related to the Pharmaceutical industry is available in its catalogue.

Stakeholder Opinions: Hepatitis C - Small-molecule antivirals pave the way for triple therapy

To order this report:

www.reportlinker.com/p074963/2008/02/Stakeholder-Opinions- Hepatitis-C-Small-molecule-antivirals-pave-the-way-for- triple-therapy.html

Research and Development activity in the Hepatitis C arena continue to be high. The market still holds many areas of unmet medical needs: while existing therapies provide good efficacy for about half of the patient population, side effects and limited efficacy in other patients offer much room for improvement. Several development setbacks over the past 18 months highlight the obstacles in R&D.

In-depth analysis of hepatitis C patient potential and dynamics across the major Western marketsThorough assessment of unmet needs and shortfalls of current HCV therapyReview of current clinical trial practice and key drug classes in development for hepatitis CIn-depth discussion of novel hepatitis C pipeline candidates and assessment of their potential in HCV therapy

Due to the suboptimal efficacy and safety profile of current standard HCV therapy, there is a large unmet need for drugs with an improved clinical profile. Experts agree that add-on therapy currently seems more promising than interferon or ribavirin replacement approaches.

Recent clinical data on small-molecule polymerase and protease inhibitors has sparked high hopes for improving SVR rates through triple therapy. Vertex's telaprevir, Schering Plough's boceprevir and Roche's R-1626 currently show the most promising profiles.

Further strategies in HCV drug development include host enzyme inhibitors and non-interferon immunomodulators. However, although theoretically highly promising, most candidates are in very early stages of development and not expected to reach the market soon.

Review the epidemiological and clinical factors driving new product decisions in hepatitis C as well as unmet needs with current treatment options.Gain insight through a detailed discussion of key pipeline candidates in late-stage development for hepatitis C.Understand where concerns and future opportunities lie by learning about the views of key hepatitis B opinion leaders.

Table of Contents

ABOUT DATAMONITOR HEALTHCARE 2

About the Infectious Diseases pharmaceutical analysis team 2

CHAPTER 1 EXECUTIVE SUMMARY 3

Scope of the analysis 3

Datamonitor insight into the Hepatitis C market 3

CHAPTER 2 DISEASE BACKGROUND AND CURRENT TREATMENT 7

HCV virology 7

Chronic HCV infection silently progresses to liver cirrhosis and cancer over prolonged periods of time 8

Interferon and ribavirin are the standard treatment for HCV 10

The current standard of care therapy - Peg-IFN alfa plus ribavirin - has a suboptimal tolerability and efficacy profile 11

Depending on their response to standard therapy, patients can be divided in different groups 12

Key unmet needs include HCV genotype 1 infection, non-response to current therapy and improved drug tolerability 15

CHAPTER 3 PATIENT POTENTIAL 18

HCV is a major health concern with 180 million people infected globally 18

Intravenous drug users and people who received blood transfusions before 1990 are at highest risk of infection 20

The number of CHC patients seeking treatment is expected to peak within the next 10-20 years 22

Across the 7MM, immigration from high prevalence countries influences overall prevalence rates for HCV 22

HCV genotype 1, which is particularly hard to treat, accounts for the majority of infections in the 7MM 23

The prevalence of genotypes varies by country 23

Whereas SVR rates are high for genotypes 2 and 3, genotypes 1 and 4 are much harder to treat 25

Patients with an African background show poorer treatment outcomes if they suffer from genotype 1 25

The treatment of HIV/HCV co-infected patients is particularly challenging 26

There are few treatment options for the large population of non-responders and relapsers 28

The high incidence of post-transplant HCV re-infection has created an important niche market 32

CHAPTER 4 R&D APPROACH 33

Of the drug classes are in development for HCV, small molecule antivirals show best prospects 33

Multiple different drug classes are being developed for use in HCV 33

'Add-on' therapy to current standard treatment is the most promising approach in HCV drug development 36

Developmental drug strategies 38

Due to the late characterization of the hepatitis C virus, drug development has been slow 41

Future HCV therapy is likely to involve combinations of at least three drugs 42

Current clinical trials focus on achieving higher SVR rates in genotype-1 patients and non-responders 43

In late-stage trials, comparison with peginterferon/ribavirin is a must for new drug candidates 44

Trials are mostly conducted in genotype-1 patients 45

The achievement of a sustained virological response (SVR) is the key endpoint in both HCV clinical trials and therapy 45

CHAPTER 5 INTERFERONS 48

Interferons have a non-specific, broad antiviral activity 48

The mechanism of Interferon alfa against HCV infection has not been elucidated 48

Standard interferons were first in class but have poor efficacy as monotherapy 48

Pegylated interferons in combination with ribavirin have become established as standard therapy 49

Pipeline efforts concentrate on long-acting formulations of interferon alfa with better tolerability 49

Pipeline summary 50

Albuferon (Human Genome Sciences/Novartis) - threatening the leading position of the peginterferons 52

Profile 52

Key clinical trials 52

Datamonitor analysis 58

IFNalpha-2b XL (Flamel Technologies) - more results needed to confirm positive top-line data 59

Profile 59

Key clinical trials 60

Datamonitor analysis 61

Locteron (OctoPlus/Biolex Therapeutics) - high EVR rates and good safety profile raise high hopes 61

Profile 61

Key clinical trials 61

Datamonitor analysis 63

Omega Interferon (Intarcia) - potential only lies in sustained release formulation 63

CHAPTER 6 SMALL MOLECULE ANTIVIRALS 64

Due to the insufficient efficacy of current HCV therapy, targeted antivirals are a popular approach for new HCV therapies 64

Pipeline summary 65

HCV NS5B polymerase inhibitors - R-1626 leading the way following late-stage pipeline failures 67

Rationale for HCV NS5B polymerase inhibitors 67

Inhibition of the NS5B polymerase specifically blocks HCV replication at an early stage 67

Nucleoside and non-nucleoside inhibitors block polymerase activity by different mechanisms 67

Pipeline overview 68

R-1626 (Roche) - positive interim Phase II results sparking high hopes 70

Profile 70

Key clinical trials 70

Datamonitor analysis 73

Other HCV polymerase inhibitors - Gilead and Roche are benefiting from Novartis's and Wyeth's trial failures 74

GS-9190 (Gilead) - Phase I trial demonstrates antiviral activity and good pharmacokinetics 74

R-7128 (Roche/Pharmasset) - trials evaluating combination with standard therapy in progress following positive Phase I results 75

NS3/4A protease inhibitors - Telaprevir facing challenges 76

Rationale for HCV NS3/4A protease inhibitors 76

The NS3 protease is essential for viral replication 76

The HCV protease as a drug target: ideal in theory, difficult in practice 77

Combination therapy with pegylated interferons and/or other antivirals will be the preferred regimen for protease inhibitors to control resistances 77

Pipeline overview 78

VX-950 (telaprevir; Vertex) - handicapped by dosing and resistances 80

Profile 80

Key clinical trial overview 80

Datamonitor analysis 84

SCH 503034 (boceprevir; Schering-Plough) - emerging as competitor for VX-950 87

Product overview 87

Key clinical trial overview 87

Datamonitor analysis 91

Other HCV protease inhibitors - two promising newcomers in Phase I 92

TMC435350 (Medivir/Johnson & Johnson) 92

ITMN-191 (Roche/InterMune) 92

Other small molecule antivirals - uncertain future for taribavirin 93

Pipeline overview 93

Taribavirin (Viramidine; Valeant Pharmaceuticals) - Phase IIb results will determine fate of the drug following VISER-1 and VISER-2 failures 94

Profile 94

Key clinical trials 94

Datamonitor assessment 98

KPE02003002 (Kemin Pharma) - no updates since 2004 99

CHAPTER 7 IMMUNOMODULATORS (NON-INTERFERON) 101

Immunomodulators are mostly developed as add-ons to existing therapy, using HCV as a secondary indication 101

Pipeline summary 102

Product profiles - best outlook for civacir 104

Zadaxin (SciClone) 104

Civacir (Nabi Biopharmaceuticals/Kedrion) 104

IM-862 (Implicit Bioscience) 105

IPH 1101 (Innate Pharma) 105

KRN-7000 (Kirin) 105

SCV-07 105

Therapeutic vaccines - a long way to go 106

IC-41 (Intercell AG) - more long-term data needed 107

Profile 107

Key clinical trial overview 108

Datamonitor analysis 110

HCV vaccine (Novartis/CSL) - no progress reported since 2004 111

CHAPTER 8 HOST ENZYME INHIBITORS 112

The main role for host-enzyme inhibitors will be as add-on to standard therapy rather than as monotherapy 112

Pipeline summary 112

Product profiles - Most candidates are still in early stages 114

Celgosivir (Migenix) 114

Profile 114

Key clinical trials 114

Datamonitor assessment 116

NIM-811 (Novartis) 117

Debio-025 (Debiopharm) 117

VGX-410C (mifepristone; VGX Pharmaceuticals) 118

Alinia (nitazoxanide; Romark Laboratories) 118

APPENDIX A 119

Bibliography 119

Report methodology 131

APPENDIX B 133

About Datamonitor 133

About Datamonitor Healthcare 133

Datamonitor Healthcare's therapy area capabilities 134

About the Infectious Diseases analysis team 135

Key therapy team members 136

Holger Rovini, Head of Respiratory and Infectious Diseases 136

Hedwig Kresse, Analyst, Infectious Diseases 136

Disclaimer 136

List of Tables

Table 1: Interferons and ribavirin are the only marketed HCV antivirals, 2007 10

Table 2: HIV mono-infected and HIV/HCV co-infected populations, 7MM, 2007 27

Table 3: Key trials for therapy in nonresponders to previous treatment with peginterferon / ribavirin 30

Table 4: Mode of action of developmental immunomodulators (non-IFN), 2007 33

Table 5: Mode of action of developmental interferons, 2007 34

Table 6: Mode of action of developmental small molecule antivirals, 2007 34

Table 7: Mode of action of developmental host enzyme inhibitors, 2007 35

Table 8: Key endpoints used in clinical trial design for HCV 47

Table 9: HCV pipeline overview - late-stage interferons, 2007 51

Table 10: Albuferon - ACHIEVE 1 trial design 53

Table 11: Albuferon - ACHIEVE 2/3 trial design 54

Table 12: Albuferon - Phase IIb (treatment-naïve) trial design and results 56

Table 13: Albuferon - Phase II (nonresponder) trial design and results 58

Table 14: Locteron - Phase IIa clinical trial design and results 62

Table 15: HCV pipeline overview -- late-stage small molecule antivirals, 2007 66

Table 16: HCV pipeline overview - NS5B polymerase inhibitors, 2007 69

Table 17: R-1626 - Phase IIa clinical trial overview and interim results 71

Table 18: R-1626 - Phase IIb clinical trial overview and interim results 72

Table 19: HCV pipeline overview - NS3/4A protease inhibitors, 2007 79

Table 20: Telaprevir -PROVE 1 study design and interim results 81

Table 21: Telaprevir - PROVE 2 study design and interim results 83

Table 22: Telaprevir - PROVE 3 study design 84

Table 23: Boceprevir - SPRINT-1 study design and preliminary results 89

Table 24: Boceprevir - Phase II study design and preliminary results 91

Table 25: HCV pipeline overview - late-stage other antivirals, 2007 93

Table 26: Taribavirin - VISER-1 Phase III study design and results 95

Table 27: Taribavirin - VISER-2 Phase III study design and results 97

Table 28: Taribavirin - Phase IIb trial design 98

Table 29: HCV pipeline overview - immunomodulators (non-IFN), 2007 103

Table 30: HCV pipeline - late-stage therapeutic vaccines, 2007 107

Table 31: IC-41 - Phase II monotherapy trial overview and interim results 108

Table 32: IC-41 - Phase II combination trial overview and interim results 110

Table 33: HCV pipeline - late-stage host enzyme inhibitors, 2007 113

Table 34: Celgosivir - Phase II combination trial design and results 115

List of Figures

Figure 1: HCV - genome organisation 8

Figure 2: HCV - course of disease 9

Figure 3: Efficacy of Pegasys + Copegus by HCV genotype 11

Figure 4: HCV - patient classification by response to treatment 14

Figure 5: HCV - key unmet needs 15

Figure 6: HCV diagnosis, 7MM, 2004 17

Figure 7: HCV - global disease prevalence and infection numbers 18

Figure 8: HCV prevalence and potential patient population across the 7MM, 2007 19

Figure 9: Sources of infection for HCV patients; US, 2006 21

Figure 10: HCV genotype split by country; Europe, US and Japan, 2007 25

Figure 11: Late-stage HCV drug pipeline (Phase II and III) by class, December 2007 36

Figure 12: Strategies for HCV drug development 37

Figure 13: The HCV NS3-encoded serine protease cleaves the non-structural HCV proteins 76

Stakeholder Opinions: Hepatitis C - Small-molecule antivirals pave the way for triple therapy

To order this report:

www.reportlinker.com/p074963/2008/02/Stakeholder-Opinions- Hepatitis-C---Small-molecule-antivirals-pave-the-way-for-triple- therapy.html

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Source: Business Wire

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